4,6-pyrimidinylene derivatives and uses thereof

ABSTRACT

The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., lung cancer, breast cancer, leukemia, lymphoma, melanoma, multiple myeloma, Ewing&#39;s sarcoma, osteosarcoma, brain cancer, neuroblastoma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase (e.g. a protein kinase (e.g. a cyclin-dependent kinase (CDK) (e.g. CDK7, CDK12, or CDK13) or a lipid kinase such as a phosphatidylinositol-5-phosphate 4-kinase (PIP4K) (e.g., PI5P4Kα, PI5P4Kβ, or PI5P4Kγ)) in the subject.

RELATED APPLICATION

The present application claims priority under 35 U.S.C. § 119(e) to U.S.provisional application, U.S. Ser. No. 62/185,334, filed Jun. 26, 2015,which is incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under grant numberR01CA197329 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

Lung cancer is the leading cancer killer worldwide accounting for 1.37million deaths annually. In the United States, lung cancer causes moredeaths than the next three most common cancers combined (colon, breastand pancreatic) and in 2014, an estimated 159,260 Americans will diefrom lung cancer. Lung cancer arises as a result of environmentalexposures, such as smoking, combined with genetic alterations such asderegulation of oncoproteins, including Myc and RAS, and loss of tumorsuppressors, such as p53. The vast majority of patients that developlung cancer will have non-small cell lung cancer (NSCLC), and 50% ofpatients will initially present with advanced NSCLC, which is incurableusing currently available therapies. The median survival of patientswith advanced NSCLC treated with chemotherapy is 8-10 months.

A major therapeutic goal in lung cancer is to identify agents againsttargets that are critical to the growth of lung cancers. This has beenclinically achieved for patients that harbor activating mutations inEGFR or chromosomal translocations such as EML4-ALK using selectiveATP-competitive kinase inhibitors. Unfortunately the duration ofresponse to targeted kinase inhibitors is typically less than 2 years,and most lung tumors do not express an oncogene that is targeted by anavailable drug. For example, loss of p53 is a common event in lungcancer, but there are currently limited drugs that can exploit its loss.

Phosphatidylinositol 4,5-bisphosphate (PIP₂) is a membrane bound lipidmolecule with the ability to affect a wide array of signaling pathwaysthat regulate different cellular processes (Camilli et al., Science,1996, 271: 1533-1539). PIP₂ is used as a precursor to generate thesecond messengers PIP₃, DAG, and IP₃, indispensable molecules forsignaling events generated by membrane receptors. However, PIP₂ can alsodirectly regulate a vast array of proteins and is emerging as a crucialmessenger with the potential to distinctly modulate biological processescritical for both normal and pathogenic cell physiology (Martin, T. F.J. (1998) Annu. Rev. Cell Dev. Biol. 14, 231-264). PIP₂ directlyassociates with effector proteins via unique phosphoinositide bindingdomains, altering their localization and/or enzymatic activity. Thespatial and temporal generation of PIP₂ synthesized by thephosphatidylinositol phosphate kinases (PIPKs) tightly regulates theactivation of receptor signaling pathways, endocytosis and vesicletrafficking, cell polarity, focal adhesion dynamics, actin assembly, and3′ mRNA processing (Balla et al., Phosphoinositides I: Enzymes ofSynthesis and Degradation, 2012, Chapter 2, PIP Kinases from the CellMembrane to the Nucleus, p 25). Two types of PIP kinases have beenidentified, type I and type II PI(4)P 5-kinases (Fruman et al., Annu.Rev. Biochem., 1998, 67: 481-507). Type I phosphorylates PI(4)P at the5-position to make PI(4,5)P2 and type II can phosphorylate PI(5)P andPI(3)P at the 4-position to make PI(4,5)P2 and PI(3,4)P2.

Recently, it has been discovered that RNAi-mediated depletion of twotype II PIP kinases, PIP4K2A and PIP4K2B, selectively inhibited theproliferation of TP53 mutant breast cancer cell line (BT474 cells) whilecells that were wild-type for TP53 were unaffected (Emerling et al.,Cell, 2013, 155: 844-857). These kinases phosphorylate the lipidphosphatidylinositol-5-phosphate (PI-5-P) at the 4-position of theinositol ring to generate phosphatidylinositol-4,5-bisphosphate(PI-4,5-P2) and are in the same kinase family as the PI3 kinases whichare now targeted by a number of clinical stage drugs. Genetic studies inmice demonstrate that homozygous germline deletion of PIP4K2B results inhealthy mice with a normal life span, while combined deletion of PIP4K2Band TP53 results in early embryonic lethality (FIG. 1) (Rameh et al.,Nature, 1997, 390: 192-196). Mice expressing one allele of PIP4K2B andhomozygous deletion of PIP4K2A and TP53 are viable and exhibit adramatic reduction in cancers and an extended lifespan compared to theirlittermates that were TP53 deleted with wild type PIP4K2A. These studiessuggest that PIP4K2A/B becomes essential when TP53 function is lost.Therefore, small molecule inhibitors of PIP4K2A/B may hold promise as atherapeutic agent for treating cancer.

SUMMARY OF THE INVENTION

The phosphoinositide family of lipids includes seven derivatives ofhosphatidylinositol (PI) that are formed through the phosphorylation ofthe 3-, 4-, and 5-positions on the inositol ring (Emerling et al., Cell,2013, 155: 844-857). Phosphoinositides have distinct biological rolesand regulate many cellular processes, including proliferation survival,glucose uptake, and migration. Phosphoinositide kinases, phosphatasesand phospholipases, spatially and temporally regulate the generation ofthe different phosphoinositide species, which localize to differentsubcellular compartments. phosphorylation of lipidphosphatidylinositol-5-phosphate (PI-5-P) at the 4-position to generatephosphatidylinositol-4,5-bisphosphate (PI-4,5-P₂) is catalyzed by theenzymes PIP4K2A, B and C. Germ line deletion of PIP4K2A and PIP4K2B inmice suppresses tumor formation in the context of TP53 deletion (Ramehet al., Nature, 1997, 390: 192-196). Loss or mutations in the tumorsuppressor gene TP53 (encoding p53) are one of the most frequent eventsin cancer. Clinical and functional studies have unequivocally validatedthe functional importance of the loss of p53 in cancer. Therefore, it isadvantageous to develop PIP4K2A and/or PIP4K2B inhibitors to providetherapeutic benefit in cancers, for example, TP53-deleted tumors.

The present invention provides compounds of Formula (I), andpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,prodrugs, and compositions thereof. The compounds of Formula (I), andpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,prodrugs, and compositions thereof, can inhibit the activity of akinase. In certain embodiments, the kinase is a protein kinase. Incertain embodiments, the protein kinase is a CDK (e.g. cyclin-dependentkinases (CDKs)). In certain embodiments, the kinase is a lipid kinase.In certain embodiments, the lipid kinase is a phosphatidylinositolphosphate kinase (PIPK). In certain embodiments, the PIPK is PIP4K,catalyzing phosphorylation of lipid phosphatidylinositol-5-phosphate(PI-5-P) at the 4-position to generatephosphatidylinositol-4,5-bisphosphate (PI-4,5-P₂). In some embodiments,the PIP4K is class I PIP4K, i.e. PIP4K1. In some embodiments, the PIP4Kis class II PIP4K, i.e. PIP4K2. In some embodiments, the PIP4K2 isPIP4K2A protein. In some embodiments, the PIP4K2 is PIP4K2B protein. Insome embodiments, the PIP4K2 is PIP4K2C protein. In certain embodiments,the compound of Formula (I) is selective for a lipid kinase compared toother kinases. In certain embodiments, the compound of Formula (I) isselective for PIP4K compared to other kinases.

The present invention further provides methods of using the inventivecompounds, and pharmaceutically acceptable salts, solvates, hydrates,polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeledderivatives, prodrugs, and compositions thereof, to study the inhibitionof a kinase (e.g., PIP4K) and as therapeutics for the prevention and/ortreatment of diseases associated with overexpression and/or aberrantactivity of a kinase (e.g., PIP4K). In certain embodiments, theinventive compounds are used for the prevention and/or treatment ofproliferative diseases (e.g., cancers (e.g., lung cancer, breast cancer,leukemia, lymphoma, melanoma, multiple myeloma, Ewing's sarcoma,osteosarcoma, brain cancer, neuroblastoma), benign neoplasms,angiogenesis, inflammatory diseases, autoinflammatory diseases, andautoimmune diseases) in a subject.

In one aspect, the present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein Ring A, L¹, L², R^(B1), R^(B2), X, R^(A),R^(C), R^(D), R^(E), n, and p are as defined herein.

In certain embodiments, a compound of Formula (I) is of Formula (II):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is Formula (III):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is Formula (IV):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is Formula (V):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is Formula (VI):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, or prodrug thereof, andoptionally a pharmaceutically acceptable excipient. In certainembodiments, the pharmaceutical compositions described herein include atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. The pharmaceutical composition may be useful fortreating and/or preventing a proliferative disease (e.g., cancer) or aninfectious disease.

In another aspect, the present invention provides methods for treatingand/or preventing proliferative diseases. Exemplary proliferativediseases include cancer (e.g., lung cancer, breast cancer, leukemia,lymphoma, melanoma, multiple myeloma, Ewing's sarcoma, osteosarcoma,brain cancer, neuroblastoma), benign neoplasm, angiogenesis,inflammatory diseases, autoinflammatory diseases, and autoimmunediseases. In certain embodiments, the cancer has one or more mutations.In certain embodiments, the cancer is TP53-deleted cancer. In otherembodiments, the present invention provides methods for treating and/orpreventing an infectious disease (e.g., a viral infection).

Another aspect of the invention relates to methods of modulating theactivity of a kinase (e.g., PIP4K (e.g., PIP4K2) enzyme) in a biologicalsample or subject. In certain embodiments, the method involves theselective inhibition of the PIP4K enzyme over other kinases. In certainembodiments, the method involves the selective inhibition of the PIP4K2enzyme over other kinases.

The present invention also provides methods of inhibiting cell growth ina biological sample or subject.

Another aspect of the invention relates to methods of screening alibrary of compounds (e.g., compounds of Formula (I)) to identify one ormore compounds useful in the treatment of a proliferative disease (e.g.,cancer (e.g., lung cancer, breast cancer, leukemia, lymphoma, melanoma,multiple myeloma, Ewing's sarcoma, osteosarcoma, brain cancer,neuroblastoma), benign neoplasm, angiogenesis, inflammatory diseases,autoinflammatory diseases, and autoimmune diseases) or an infectiousdisease (e.g., viral infection) in a subject, in inhibiting a kinase(e.g., PIP4K enzyme), or in inhibiting cell growth.

In yet another aspect, the present invention provides compounds ofFormula (I), and pharmaceutically acceptable salts, solvates, hydrates,polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeledderivatives, prodrugs, and compositions thereof, for use in thetreatment of a proliferative disease in a subject.

In yet another aspect, the present invention provides compounds ofFormula (I), and pharmaceutically acceptable salts, solvates, hydrates,polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeledderivatives, prodrugs, and compositions thereof, for use in thetreatment or prevention of an infectious disease in a subject. Incertain embodiments, the infectious disease is a viral infection.

Another aspect of the present invention relates to kits comprising acontainer with a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, or prodrug thereof, or apharmaceutical composition thereof. The kits of the invention mayinclude a single dose or multiple doses of a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, or a pharmaceutical composition thereof. The providedkits may be useful for the treatment and/or prevention of aproliferative disease (e.g., cancer (e.g., lung cancer, breast cancer,leukemia, lymphoma, melanoma, multiple myeloma, Ewing's sarcoma,osteosarcoma, brain cancer, neuroblastoma), benign neoplasm,angiogenesis, inflammatory diseases, autoinflammatory diseases, andautoimmune diseases) or an infectious disease in a subject. In certainembodiments, the kits described herein further include instructions foradministering the compound of Formula (I), or the pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, or prodrug thereof, orthe pharmaceutical composition thereof.

The details of one or more embodiments of the invention are set forthherein. Other features, objects, and advantages of the invention will beapparent from the Detailed Description, the Examples, and the Claims.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987. The disclosure is not intended to belimited in any manner by the exemplary listing of substituents describedherein.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The disclosure additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₈, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆.

The term “aliphatic” includes both saturated and unsaturated, straightchain (i.e., unbranched), branched, acyclic, cyclic, or polycyclicaliphatic hydrocarbons, which are substituted or unsubstituted with oneor more functional groups. As will be appreciated by one of ordinaryskill in the art, “aliphatic” is intended herein to include, but is notlimited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, andcycloalkynyl moieties. Thus, the term “alkyl” includes straight,branched and cyclic alkyl groups. An analogous convention applies toother generic terms such as “alkenyl”, “alkynyl”, and the like.Furthermore, the terms “alkyl”, “alkenyl”, “alkynyl”, and the likeencompass both substituted and unsubstituted groups. In certainembodiments, “lower alkyl” is used to indicate those alkyl groups(cyclic, acyclic, substituted, unsubstituted, branched or unbranched)having 1-6 carbon atoms.

In certain embodiments, the alkyl, alkenyl, and alkynyl groups employedin the disclosure contain 1-20 aliphatic carbon atoms. In certain otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-10 aliphatic carbon atoms. In yet otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-8 aliphatic carbon atoms. In still otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-6 aliphatic carbon atoms. In yet other embodiments,the alkyl, alkenyl, and alkynyl groups employed in the disclosurecontain 1-4 carbon atoms. Illustrative aliphatic groups thus include,but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, —CH₂-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl,isobutyl, tert-butyl, cyclobutyl, —CH₂-cyclobutyl, n-pentyl, sec-pentyl,isopentyl, tert-pentyl, cyclopentyl, —CH₂-cyclopentyl, n-hexyl,sec-hexyl, cyclohexyl, —CH₂-cyclohexyl moieties and the like, whichagain, may bear one or more substituents. Alkenyl groups include, butare not limited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, and the like. Representative alkynyl groupsinclude, but are not limited to, ethynyl, 2-propynyl (propargyl),1-propynyl, and the like.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁₋₁₀alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.,unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)),unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu),unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl(sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certainembodiments, the alkyl group is a substituted C₁₋₁₀ alkyl (such assubstituted C₁₋₆ alkyl, e.g., benzyl (Bn) or —CF₃).

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl. Inan alkenyl group, a C═C double bond for which the stereochemistry is notspecified (e.g., —CH═CHCH₃₀

may be an (E)- or (Z)-double bond.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclic ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclic ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₁₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system,such as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclic ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclicring, or ring systems wherein the heterocyclic ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclic ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclic ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 membered,non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pielectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups, wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. Unless otherwise specified, each instance of an aryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted aryl”) or substituted (a “substituted aryl”) with one ormore substituents. In certain embodiments, the aryl group isunsubstituted C₆₋₁₄ aryl. In certain embodiments, the aryl group issubstituted C₆₋₁₄ aryl.

“Aralkyl” refers to a substituted or unsubstituted alkyl groupsubstituted by a substituted or unsubstituted aryl group. In certainembodiments, the aralkyl is substituted or unsubstituted benzyl. Incertain embodiments, the aralkyl is benzyl. In certain embodiments, thearalkyl is substituted or unsubstituted phenethyl. In certainembodiments, the aralkyl is phenethyl.

“Heteroaryl” refers to a radical of a 5-10 membered, monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl, and thiophenyl.Exemplary 5-membered heteroaryl groups containing two heteroatomsinclude, without limitation, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroarylgroups containing three heteroatoms include, without limitation,triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-memberedheteroaryl groups containing four heteroatoms include, withoutlimitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl and refers to asubstituted or unsubstituted alkyl group substituted by a substituted orunsubstituted heteroaryl group.

“Unsaturated” or “partially unsaturated” refers to a group that includesat least one double or triple bond. A “partially unsaturated” ringsystem is further intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic groups (e.g., arylor heteroaryl groups). Likewise, “saturated” refers to a group that doesnot contain a double or triple bond, i.e., contains all single bonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, which are divalent linking groups, are further referred to usingthe suffix -ene, e.g., alkylene, alkenylene, alkynylene, carbocyclylene,heterocyclylene, arylene, and heteroarylene.

An atom, moiety, or group described herein may be unsubstituted orsubstituted, as valency permits, unless otherwise provided expressly.The term “optionally substituted” refers to substituted orunsubstituted.

A group is substituted or unsubstituted unless expressly providedotherwise. The term “optionally substituted” refers to being substitutedor unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are substitutedor unsubstituted (e.g., “substituted” or “unsubstituted” alkyl,“substituted” or “unsubstituted” alkenyl, “substituted” or“unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl,“substituted” or “unsubstituted” heterocyclyl, “substituted” or“unsubstituted” aryl or “substituted” or “unsubstituted” heteroarylgroup). In general, the term “substituted”, whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group(e.g., a carbon or nitrogen atom) is replaced with a permissiblesubstituent, e.g., a substituent which upon substitution results in astable compound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with allpermissible substituents of organic compounds, any of the substituentsdescribed herein that results in the formation of a stable compound. Thepresent disclosure contemplates any and all such combinations in orderto arrive at a stable compound. For purposes of this disclosure,heteroatoms such as nitrogen may have hydrogen substituents and/or anysuitable substituent as described herein which satisfy the valencies ofthe heteroatoms and results in the formation of a stable moiety. Incertain embodiments, the substituent is a carbon atom substituent. Incertain embodiments, the substituent is a nitrogen atom substituent. Incertain embodiments, the substituent is an oxygen atom substituent. Incertain embodiments, the substituent is a sulfur atom substituent.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —S₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂,—NR^(bb)P(═O)(R^(aa))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂, —P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻,—P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄, —P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃⁺X⁻, —OP(OR^(cc))₂, —OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄,—B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is acounterion;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(aa)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(aa), —SO₂OR^(aa), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is acounterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(cc) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—C(═NR^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee),—SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee),—Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee),—C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)(OR^(ee))₂, —P(═O)(R^(ee))₂,—OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl,heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(gg) groups, or two geminal R^(dd) substituents can be joined toform ═O or ═S; wherein X⁻ is a counterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆ alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(f)groups are joined to form a 3-10 membered heterocyclyl or 5-10 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion. In certain embodiments, the carbonatom substituents are independently halogen, substituted orunsubstituted C₁₋₆ alkyl, or —OR^(aa).

The term “hydroxyl” or “hydroxy” refers to the group —OH. The term“substituted hydroxyl” or “substituted hydroxyl,” by extension, refersto a hydroxyl group wherein the oxygen atom directly attached to theparent molecule is substituted with a group other than hydrogen, andincludes groups selected from —OR^(aa), —ON(R^(bb))₂, —OC(═O)SR^(aa),—OC(═O)R^(aa), —OCO₂R—, —OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa),OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa),—OSO₂R^(aa), —OSi(R^(aa))₃, —OP(R^(cc))₂, —OP(R^(cc))₃ ⁺X⁻,—OP(OR^(cc))₂, —OP(OR^(cc))₃ ⁺X⁻, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,and —OP(═O)(N(R^(bb)))₂, wherein R^(aa), R^(bb), and R^(cc) are asdefined herein.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like). Further exemplary counterions include, but arenot limited to, BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆ ⁻,B[3,5-(CF₃)₂C₆H₃]₄]⁻, B(C₆F₅)₄ ⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, and carboraneanions (e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br6)⁻). Exemplary counterions whichmay be multivalent include CO₃ ²⁻, HPO₄ ²⁻, PO₄ ³⁻, B₄O₇ ²⁻, SO₄ ²⁻,S₂O₃ ²⁻, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate,malate, malonate, gluconate, succinate, glutarate, adipate, pimelate,suberate, azelate, sebacate, salicylate, phthalates, aspartate,glutamate, and the like), and carboranes

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

“Acyl” refers to a moiety selected from the group consisting of—C(═O)R^(aa), —CHO, —CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR—, —C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), or —C(═S)SR^(aa), wherein R^(cc) andR^(bb) are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R, —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(aa), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(cc)groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa),R^(bb), R^(cc) and R^(dd) are as defined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc) and R^(dd) are as defined herein. Nitrogen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(cc)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), 3-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). Incertain embodiments, a nitrogen protecting group is Bn, BOC, Cbz, Fmoc,trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an “hydroxylprotecting group”). Oxygen protecting groups include, but are notlimited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa),—CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR—,—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R′)₃, —P(R^(cc))₂,—P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻, —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, wherein R^(aa), R^(bb), andR^(cc) are as defined herein. Oxygen protecting groups are well known inthe art and include those described in detail in Protecting Groups inOrganic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, JohnWiley & Sons, 1999, incorporated herein by reference.

Exemplary oxygen atom substituents include, but are not limited to,—R^(aa), —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R, —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R′)₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R′)₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. In certain embodiments, the oxygen atom substituent present onan oxygen atom is an oxygen protecting group (also referred to as ahydroxyl protecting group). Oxygen protecting groups are well known inthe art and include those described in detail in Protecting Groups inOrganic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, JohnWiley & Sons, 1999, incorporated herein by reference. Exemplary oxygenprotecting groups include, but are not limited to, methyl,t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM), methylthiomethyl(MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM),benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM),(4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl,4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM),2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl,2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP),3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl,4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl,4-methoxytetrahydrothiopyranyl S,S-dioxide,1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP),1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, a-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts). In certain embodiments, an oxygen protecting group is silyl,TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl,pivaloyl, or benzoyl.

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a “thiol protectinggroup”). Sulfur protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR—,—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(cc))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(cc))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Sulfur protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference. In certain embodiments, a sulfur protecting group isacetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl,or triphenylmethyl.

A “hydrocarbon chain” refers to a substituted or unsubstituted divalentalkyl, alkenyl, or alkynyl group. A hydrocarbon chain includes (1) oneor more chains of carbon atoms immediately between the two radicals ofthe hydrocarbon chain; (2) optionally one or more hydrogen atoms on thechain(s) of carbon atoms; and (3) optionally one or more substituents(“non-chain substituents,” which are not hydrogen) on the chain(s) ofcarbon atoms. A chain of carbon atoms consists of consecutivelyconnected carbon atoms (“chain atoms” or “carbon units”) and does notinclude hydrogen atoms or heteroatoms. However, a non-chain substituentof a hydrocarbon chain may include any atoms, including hydrogen atoms,carbon atoms, and heteroatoms. For example, hydrocarbon chain—C^(A)H(C^(B)H₂C^(C)H₃)— includes one chain atom C^(A), one hydrogenatom on C^(A), and non-chain substituent —(C^(B)H₂C^(C)H₃). The term“C_(x) hydrocarbon chain,” wherein x is a positive integer, refers to ahydrocarbon chain that includes x number of chain atom(s) between thetwo radicals of the hydrocarbon chain. If there is more than onepossible value of x, the smallest possible value of x is used for thedefinition of the hydrocarbon chain. For example, —CH(C₂H₅)— is a C₁hydrocarbon chain, and

is a C₃ hydrocarbon chain. When a range of values is used, the meaningof the range is as described herein. For example, a C₃₋₁₀ hydrocarbonchain refers to a hydrocarbon chain where the number of chain atoms ofthe shortest chain of carbon atoms immediately between the two radicalsof the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. A hydrocarbonchain may be saturated (e.g., —(CH₂)₄—). A hydrocarbon chain may also beunsaturated and include one or more C═C and/or C° C. bonds anywhere inthe hydrocarbon chain. For instance, —CH═CH—(CH₂)₂—, —CH₂—C═C—CH₂—, and—C≡C—CH═CH— are all examples of a unsubstituted and unsaturatedhydrocarbon chain. In certain embodiments, the hydrocarbon chain isunsubstituted (e.g., —C≡C— or —(CH₂)₄—). In certain embodiments, thehydrocarbon chain is substituted (e.g., —CH(C₂H₅)— and —CF₂—). Any twosubstituents on the hydrocarbon chain may be joined to form asubstituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl ring. For instance,

and are all examples of a hydrocarbon chain. In contrast, in certainembodiments,

are not within the scope of the hydrocarbon chains described herein.When a chain atom of a C_(x) hydrocarbon chain is replaced with aheteroatom, the resulting group is referred to as a C_(x) hydrocarbonchain wherein a chain atom is replaced with a heteroatom, as opposed toa C_(x-1) hydrocarbon chain. For example,

is a C₃ hydrocarbon chain wherein one chain atom is replaced with anoxygen atom.

The term “leaving group” is given its ordinary meaning in the art ofsynthetic organic chemistry and refers to an atom or a group capable ofbeing displaced by a nucleophile. Examples of suitable leaving groupsinclude, but are not limited to, halogen (such as F, Cl, Br, or I(iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy,arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy,aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. Insome cases, the leaving group is a sulfonic acid ester, such astoluenesulfonate (tosylate, —OTs), methanesulfonate (mesylate, —OMs),p-bromobenzenesulfonyloxy (brosylate, —OBs), —OS(═O)₂(CF₂)₃CF₃(nonaflate, —ONf), or trifluoromethanesulfonate (triflate, —OTf). Insome cases, the leaving group is a brosylate, such asp-bromobenzenesulfonyloxy. In some cases, the leaving group is anosylate, such as 2-nitrobenzenesulfonyloxy. The leaving group may alsobe a phosphineoxide (e.g., formed during a Mitsunobu reaction) or aninternal leaving group such as an epoxide or cyclic sulfate. Othernon-limiting examples of leaving groups are water, ammonia, alcohols,ether moieties, thioether moieties, zinc halides, magnesium moieties,diazonium salts, and copper moieties. Further exemplary leaving groupsinclude, but are not limited to, halo (e.g., chloro, bromo, iodo) andactivated substituted hydroxyl groups (e.g., —OC(═O)SR^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R—,—OC(═NR^(bb))OR—, —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa), —OSO₂R^(aa),—OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa), —OP(═O)(R′)₂,—OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and —OP(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R are as defined herein).

Other Definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds describedherein include those derived from suitable inorganic and organic acidsand bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associatedwith a solvent, usually by a solvolysis reaction. This physicalassociation may include hydrogen bonding. Conventional solvents includewater, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and thelike. The compounds described herein may be prepared, e.g., incrystalline form, and may be solvated. Suitable solvates includepharmaceutically acceptable solvates and further include bothstoichiometric solvates and non-stoichiometric solvates. In certaininstances, the solvate will be capable of isolation, for example, whenone or more solvent molecules are incorporated in the crystal lattice ofa crystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Representative solvates include hydrates,ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R-x H₂O, wherein R is the compound,and x is a number greater than 0. A given compound may form more thanone type of hydrate, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R.0.5 H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R.2 H₂O) and hexahydrates (R.6 H₂O)).

The term “tautomers” or “tautomeric” refers to two or moreinterconvertible compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The term “polymorphs” refers to a crystalline form of a compound (or asalt, hydrate, or solvate thereof) in a particular crystal packingarrangement. All polymorphs have the same elemental composition.Different crystalline forms usually have different X-ray diffractionpatterns, infrared spectra, melting points, density, hardness, crystalshape, optical and electrical properties, stability, and solubility.Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate. Variouspolymorphs of a compound can be prepared by crystallization underdifferent conditions.

The term “co-crystal” refers to a crystalline structure composed of atleast two components. In certain embodiments, a co-crystal may contain acompound of the present invention and one or more other component,including but not limited to, atoms, ions, molecules, or solventmolecules. In certain embodiments, a co-crystal may contain a compoundof the present invention and one or more components related to saidcompound, including not limited to, an isomer, tautomer, salt, solvate,hydrate, synthetic precursor, synthetic derivative, fragment or impurityof said compound.

The term “isotopically labeled derivative” or “isotopically labeled”refers to a compound wherein one or more atoms in the compound (or in anassociated ion or molecule of a salt, hydrate, or solvate) has beenreplaced with an isotope of the same element. For the given element orposition in the molecule the isotope will be enriched, or present in ahigher percentage of all atoms of the element or of all atoms at theposition in the molecule in a sample, relative to an unlabeled variant.In certain embodiments, the enriched isotope will be a stable isotope.In certain embodiments, the enriched isotope will be an unstable orradioactive isotope (e.g., a radionuclide). In certain embodiments, theenriched isotope may be detected by a measurement technique, includingbut not limited to nuclear magnetic resonance, mass spectrometry,infrared spectroscopy, or a technique that measures radioactive decay.

The term “prodrugs” refers to compounds that have cleavable groups andbecome by solvolysis or under physiological conditions the compoundsdescribed herein, which are pharmaceutically active in vivo. Suchexamples include, but are not limited to, choline ester derivatives andthe like, N-alkylmorpholine esters and the like. Other derivatives ofthe compounds described herein have activity in both their acid and acidderivative forms, but in the acid sensitive form often offer advantagesof solubility, tissue compatibility, or delayed release in the mammalianorganism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24,Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well knownto practitioners of the art, such as, for example, esters prepared byreaction of the parent acid with a suitable alcohol, or amides preparedby reaction of the parent acid compound with a substituted orunsubstituted amine, or acid anhydrides, or mixed anhydrides. Simplealiphatic or aromatic esters, amides, and anhydrides derived from acidicgroups pendant on the compounds described herein are particularprodrugs. In some cases it is desirable to prepare double ester typeprodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters ofthe compounds described herein may be preferred.

The term “inhibition”, “inhibiting”, “inhibit,” or “inhibitor” refer tothe ability of a compound to reduce, slow, halt or prevent activity of aparticular biological process (e.g., activity of a bromodomain and/or abromodomain-containing protein) in a cell relative to vehicle.

When a compound, pharmaceutical composition, method, use, or kit isreferred to as “selectively,” “specifically,” or “competitively” bindinga first protein or a first chromatin, the compound, pharmaceuticalcomposition, method, use, or kit binds the first protein or the firstchromatin with a higher binding affinity (e.g., not less than about2-fold, not less than about 5-fold, not less than about 10-fold, notless than about 30-fold, not less than about 100-fold, not less thanabout 1,000-fold, or not less than about 10,000-fold) than binding asecond protein or second chromatin that is different from the firstprotein and the first chromatin. When a compound, pharmaceuticalcomposition, method, use, or kit is referred to as “selectively,”“specifically,” or “competitively” modulating (e.g., increasing orinhibiting) the activity of a bromodomain-containing protein, thecompound, pharmaceutical composition, method, use, or kit modulates theactivity of the bromodomain-containing protein to a greater extent(e.g., not less than about 2-fold, not less than about 5-fold, not lessthan about 10-fold, not less than about 30-fold, not less than about100-fold, not less than about 1,000-fold, or not less than about10,000-fold) than the activity of at least one protein that is differentfrom the bromodomain-containing protein.

The term “aberrant activity” refers to activity deviating from normalactivity, that is, abnormal activity. The term “increased activity”refers to activity higher than normal activity.

The terms “composition” and “formulation” are used interchangeably.

A “subject” to which administration is contemplated refers to a human(i.e., male or female of any age group, e.g., pediatric subject (e.g.,infant, child, or adolescent) or adult subject (e.g., young adult,middle-aged adult, or senior adult)) or non-human animal. In certainembodiments, the non-human animal is a mammal (e.g., primate (e.g.,cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g.,cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g.,commercially relevant bird, such as chicken, duck, goose, or turkey)).In certain embodiments, the non-human animal is a fish, reptile, oramphibian. The non-human animal may be a male or female at any stage ofdevelopment. The non-human animal may be a transgenic animal orgenetically engineered animal. A “patient” refers to a human subject inneed of treatment of a disease.

The term “biological sample” refers to any sample including tissuesamples (such as tissue sections and needle biopsies of a tissue); cellsamples (e.g., cytological smears (such as Pap or blood smears) orsamples of cells obtained by microdissection); samples of wholeorganisms (such as samples of yeasts or bacteria); or cell fractions,fragments or organelles (such as obtained by lysing cells and separatingthe components thereof by centrifugation or otherwise). Other examplesof biological samples include blood, serum, urine, semen, fecal matter,cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus,biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy),nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccalswabs), or any material containing biomolecules that is derived fromanother biological sample.

The terms “administer,” “administering,” or “administration” refers toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing a compound described herein, or a composition thereof, into,in, or on a subject.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of adisease described herein. In some embodiments, treatment may beadministered after one or more signs or symptoms of the disease havedeveloped or have been observed. In other embodiments, treatment may beadministered in the absence of signs or symptoms of the disease. Forexample, treatment may be administered to a susceptible subject prior tothe onset of symptoms (e.g., in light of a history of symptoms and/or inlight of exposure to a pathogen). Treatment may also be continued aftersymptoms have resolved, for example, to delay or prevent recurrence.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response, i.e., treating thecondition. As will be appreciated by those of ordinary skill in thisart, the effective amount of a compound described herein may varydepending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the modeof administration, and the age and health of the subject. In certainembodiments, an effective amount is a therapeutically effective amount.In certain embodiments, an effective amount is a prophylactic treatment.In certain embodiments, an effective amount is the amount of a compounddescribed herein in a single dose. In certain embodiments, an effectiveamount is the combined amounts of a compound described herein inmultiple doses.

A “therapeutically effective amount” of a compound described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition or to delay or minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms, signs,or causes of the condition, and/or enhances the therapeutic efficacy ofanother therapeutic agent.

A “prophylactically effective amount” of a compound described herein isan amount sufficient to prevent a condition, or one or more symptomsassociated with the condition or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the condition. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, diseases associated with angiogenesis,inflammatory diseases, and autoimmune diseases.

The term “angiogenesis” refers to the physiological process throughwhich new blood vessels form from pre-existing vessels. Angiogenesis isdistinct from vasculogenesis, which is the de novo formation ofendothelial cells from mesoderm cell precursors. The first vessels in adeveloping embryo form through vasculogenesis, after which angiogenesisis responsible for most blood vessel growth during normal or abnormaldevelopment. Angiogenesis is a vital process in growth and development,as well as in wound healing and in the formation of granulation tissue.However, angiogenesis is also a fundamental step in the transition oftumors from a benign state to a malignant one, leading to the use ofangiogenesis inhibitors in the treatment of cancer. Angiogenesis may bechemically stimulated by angiogenic proteins, such as growth factors(e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g.,excessive or insufficient) angiogenesis that amounts to and/or isassociated with a disease.

The terms “neoplasm” and “tumor” are used herein interchangeably andrefer to an abnormal mass of tissue wherein the growth of the masssurpasses and is not coordinated as in the growth of normal tissue. Aneoplasm or tumor may be “benign” or “malignant,” depending on thefollowing characteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An exemplary pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue. Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites. The term “metastasis,” “metastatic,” or“metastasize” refers to the spread or migration of cancerous cells froma primary or original tumor to another organ or tissue and is typicallyidentifiable by the presence of a “secondary tumor” or “secondary cellmass” of the tissue type of the primary or original tumor and not ofthat of the organ or tissue in which the secondary (metastatic) tumor islocated. For example, a prostate cancer that has migrated to bone issaid to be metastasized prostate cancer and includes cancerous prostatecancer cells growing in bone tissue.

The term “cancer” refers to a class of diseases characterized by thedevelopment of abnormal cells that proliferate uncontrollably and havethe ability to infiltrate and destroy normal body tissues. See, e.g.,Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins:Philadelphia, 1990. Exemplary cancers include, but are not limited to,hematological malignancies. Additional exemplary cancers include, butare not limited to, acoustic neuroma; adenocarcinoma; adrenal glandcancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma,lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benignmonoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma);bladder cancer; breast cancer (e.g., adenocarcinoma of the breast,papillary carcinoma of the breast, mammary cancer, medullary carcinomaof the breast, triple negative breast cancer (TNBC)); brain cancer(e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma,oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor;cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma;chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer,rectal cancer, colorectal adenocarcinoma); connective tissue cancer;epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi'ssarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer(e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing'ssarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma);familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germcell cancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chaindisease, gamma chain disease, mu chain disease; hemangioblastoma;hypopharynx cancer; inflammatory myofibroblastic tumors; immunocyticamyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor,renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC),malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, smallcell lung cancer (SCLC), non-small cell lung cancer (NSCLC),adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g.,systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS);mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera(PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM)a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronicmyelocytic leukemia (CML), chronic neutrophilic leukemia (CNL),hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g.,neurofibromatosis (NF) type 1 or type 2, schwannomatosis);neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor(GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovariancancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarianadenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g.,pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm(IPMN), Islet cell tumors); penile cancer (e.g., Paget's disease of thepenis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT);plasma cell neoplasia; paraneoplastic syndromes; intraepithelialneoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectalcancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g.,squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basalcell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); softtissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma,malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma,fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestinecancer; sweat gland carcinoma; synovioma; testicular cancer (e.g.,seminoma, testicular embryonal carcinoma); thyroid cancer (e.g.,papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC),medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvarcancer (e.g., Paget's disease of the vulva).

The term “hematological malignancy” refers to tumors that affect blood,bone marrow, and/or lymph nodes. Exemplary hematological malignanciesinclude, but are not limited to, leukemia, such as acute lymphoblasticleukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia(AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML)(e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL)(e.g., B-cell CLL, T-cell CLL)); lymphoma, such as Hodgkin lymphoma (HL)(e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g.,B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuselarge B-cell lymphoma (DLBCL, e.g., activated B-cell (ABC) DLBCL(ABC-DLBCL))), follicular lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginalzone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT)lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zoneB-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt'slymphoma, Waldenstram's macroglobulinemia (WM, lymphoplasmacyticlymphoma), hairy cell leukemia (HCL), immunoblastic large cell lymphoma,precursor B-lymphoblastic lymphoma, central nervous system (CNS)lymphoma (e.g., primary CNS lymphoma and secondary CNS lymphoma); andT-cell NHL, such as precursor T-lymphoblastic lymphoma/leukemia,peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma(CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblasticT-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathytype T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma,and anaplastic large cell lymphoma); lymphoma of an immune privilegedsite (e.g., cerebral lymphoma, ocular lymphoma, lymphoma of theplacenta, lymphoma of the fetus, testicular lymphoma); a mixture of oneor more leukemia/lymphoma as described above; myelodysplasia; andmultiple myeloma (MM).

The term “inflammatory disease” refers to a disease caused by, resultingfrom, or resulting in inflammation. The term “inflammatory disease” mayalso refer to a dysregulated inflammatory reaction that causes anexaggerated response by macrophages, granulocytes, and/or T-lymphocytesleading to abnormal tissue damage and/or cell death. An inflammatorydisease can be either an acute or chronic inflammatory condition and canresult from infections or non-infectious causes. Inflammatory diseasesinclude, without limitation, atherosclerosis, arteriosclerosis,autoimmune disorders, multiple sclerosis, systemic lupus erythematosus,polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis,tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis,rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giantcell arteritis, progressive systemic sclerosis (scleroderma), ankylosingspondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid,diabetes (e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis,Graves' disease, Goodpasture's disease, mixed connective tissue disease,sclerosing cholangitis, inflammatory bowel disease, Crohn's disease,ulcerative colitis, pernicious anemia, inflammatory dermatoses, usualinterstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis,berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamativeinterstitial pneumonia, lymphoid interstitial pneumonia, giant cellinterstitial pneumonia, cellular interstitial pneumonia, extrinsicallergic alveolitis, Wegener's granulomatosis and related forms ofangiitis (temporal arteritis and polyarteritis nodosa), inflammatorydermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g.,poison ivy dermatitis), pneumonia, respiratory tract inflammation, AdultRespiratory Distress Syndrome (ARDS), encephalitis, immediatehypersensitivity reactions, asthma, hay fever, allergies, acuteanaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis,cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury),reperfusion injury, allograft rejection, host-versus-graft rejection,appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis,cervicitis, cholangitis, chorioamnionitis, conjunctivitis,dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis,myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis,osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis,urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis,vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, opticneuritis, temporal arteritis, transverse myelitis, necrotizingfasciitis, and necrotizing enterocolitis.

An “autoimmune disease” refers to a disease arising from aninappropriate immune response of the body of a subject againstsubstances and tissues normally present in the body. In other words, theimmune system mistakes some part of the body as a pathogen and attacksits own cells. This may be restricted to certain organs (e.g., inautoimmune thyroiditis) or involve a particular tissue in differentplaces (e.g., Goodpasture's disease which may affect the basementmembrane in both the lung and kidney). The treatment of autoimmunediseases is typically with immunosuppression, e.g., medications whichdecrease the immune response. Exemplary autoimmune diseases include, butare not limited to, glomerulonephritis, Goodpasture's syndrome,necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemiclupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemiclupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis,dermatomyositis/polymyositis, anti-phospholipid antibody syndrome,scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g.,Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren'ssyndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis,Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, andcardiomyopathy.

The term “kinase” is a type of enzyme that transfers phosphate groupsfrom high energy donor molecules, such as ATP, to specific substrates,referred to as phosphorylation. Kinases are part of the larger family ofphosphotransferases. Kinases are used extensively to transmit signalsand control complex processes in cells. Various other kinases act onsmall molecules such as lipids, carbohydrates, amino acids, andnucleotides, either for signaling or to prime them for metabolicpathways. Kinases are often named after their substrates. More than 500different protein kinases have been identified in humans. In someembodiments, the kinase is a protein kinase. A protein kinase is akinase enzyme that modifies other proteins by chemically addingphosphate groups to them (phosphorylation). In some embodiments, theprotein kinase is Cyclin dependent kinases (CDKs). CDKs are a group ofseveral different kinases involved in regulation of the cell cycle. Theyphosphorylate other proteins on their serine or threonine residues, butCDKs must first bind to a cyclin protein in order to be active. In someembodiments, the protein kinase is mitogen-activated protein kinases(MAPKs). MAP kinases (MAPKs) are a family of serine/threonine kinasesthat respond to a variety of extracellular growth signals. In someembodiments, the kinase is a lipid kinases that phosphorylate lipids inthe cell, both on the plasma membrane as well as on the membranes of theorganelles. The addition of phosphate groups can change the reactivityand localization of the lipid and can be used in signal transmission. Insome embodiments, the lipid kinase is a phosphatidylinositol kinase thatphosphorylates phosphatidylinositol species, to create species such asphosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), phosphatidylinositol3,4,5-trisphosphate (PIP3), and phosphatidylinositol 3-phosphate (PI3P).In some embodiments, the lipid kinase is sphingosine kinase (SK), alipid kinase that catalyzes the conversion of sphingosine tosphingosine-1-phosphate (SIP). In certain embodiments, the SK is SK1 orSK2. Exemplary human protein kinases include, but are not limited to,AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, ALK, ALK1, ALK2, ALK4,ALK7, AMPKa1, AMPKa2, ANKRD3, ANPa, ANPb, ARAF, ARAFps, ARG, AurA,AurAps1, AurAps2, AurB, AurBpsl, AurC, AXL, BARK1, BARK2, BIKE, BLK,BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B, BMPR2, BMX, BRAF, BRAFps, BRK,BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a, CaMK1b, CaMK1d, CaMK1g, CaMK2a,CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKK1, CaMKK2, caMLCK, CASK, CCK4, CCRK,CDC₂, CDC₇, CDK10, CDK11, CDK2, CDK3, CDK4, CDK4ps, CDK5, CDK5ps, CDK6,CDK7, CDK7ps, CDK8, CDK8ps, CDK9, CDKL1, CDKL2, CDKL3, CDKL4, CDKL5,CGDps, CHED, CHK1, CHK2, CHK2ps1, CHK2ps2, CK1a, CK1a2, CK1aps1,CK1aps2, CK1aps3, CK1d, CK1e, CK1g1, CK1g2, CK1g2ps, CK1g3, CK2a1,CK2a1-rs, CK2a2, CLIK1, CLIKIL, CLK1, CLK2, CLK2ps, CLK3, CLK3ps, CLK4,COT, CRIK, CRK7, CSK, CTK, CYGD, CYGF, DAPK1, DAPK2, DAPK3, DCAMKL1,DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK1, DMPK2, DRAK1, DRAK2, DYRK1A,DYRK1B, DYRK2, DYRK3, DYRK4, EGFR, EphA1, EphA10, EphA2, EphA3, EphA4,EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB6, Erk1,Erk2, Erk3, Erk3ps1, Erk3ps2, Erk3ps3, Erk3ps4, Erk4, Erk5, Erk7, FAK,FER, FERps, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT1ps, FLT3,FLT4, FMS, FRK, Fused, FYN, GAK, GCK, GCN2, GCN22, GPRK4, GPRK5, GPRK6,GPRK6ps, GPRK7, GSK3A, GSK3B, Haspin, HCK, HER2/ErbB2, HER3/ErbB3,HER4/ErbB4, HH498, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HRI, HRIps, HSER,HUNK, ICK, IGF1R, IKKa, IKKb, IKKe, ILK, INSR, IRAK1, IRAK2, IRAK3,IRAK4, IRE1, IRE2, IRR, ITK, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR,KHS1, KHS2, KIS, KIT, KSGCps, KSR1, KSR2, LATS1, LATS2, LCK, LIMK1,LIMK2, LIMK2ps, LKB1, LMR1, LMR2, LMR3, LOK, LRRK1, LRRK2, LTK, LYN,LZK, MAK, MAP2K1, MAP2K1ps, MAP2K2, MAP2K2ps, MAP2K3, MAP2K4, MAP2K5,MAP2K6, MAP2K7, MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7,MAP3K8, MAPKAPK2, MAPKAPK3, MAPKAPK5, MAPKAPKps1, MARK1, MARK2, MARK3,MARK4, MARKps01, MARKps02, MARKps03, MARKps04, MARKps05, MARKps07,MARKps08, MARKps09, MARKps10, MARKps11, MARKps12, MARKps13, MARKps15,MARKps16, MARKps17, MARKps18, MARKps19, MARKps20, MARKps21, MARKps22,MARKps23, MARKps24, MARKps25, MARKps26, MARKps27, MARKps28, MARKps29,MARKps30, MAST1, MAST2, MAST3, MAST4, MASTL, MELK, MER, MET, MISR2,MLK1, MLK2, MLK3, MLK4, MLKL, MNK1, MNK1ps, MNK2, MOK, MOS, MPSK1,MPSK1ps, MRCKa, MRCKb, MRCKps, MSK1, MSK12, MSK2, MSK22, MSSK1, MST1,MST2, MST3, MST3ps, MST4, MUSK, MYO3A, MYO3B, MYT1, NDR1, NDR2, NEK1,NEK10, NEK11, NEK2, NEK2ps1, NEK2ps2, NEK2ps3, NEK3, NEK4, NEK4ps, NEK5,NEK6, NEK7, NEK8, NEK9, NIK, NIM1, NLK, NRBP1, NRBP2, NuaK1, NuaK2,Obsen, Obscn2, OSR1, p38a, p38b, p38d, p38g, p70S6K, p70S6Kb, p70S6Kps1,p70S6Kps2, PAK1, PAK2, PAK2ps, PAK3, PAK4, PAK5, PAK6, PASK, PBK,PCTAIRE1, PCTAIRE2, PCTAIRE3, PDGFRa, PDGFRb, PDK1, PEK, PFTAIRE1,PFTAIRE2, PHKg1, PHKg1ps1, PHKglps2, PHKglps3, PHKg2, PIK3R4, PIM1,PIM2, PIM3, PINK1, PIP4K2A, PIP4K2B, PIPK□, PITSLRE, PKACa, PKACb,PKACg, PKCa, PKCb, PKCd, PKCe, PKCg, PKCh, PKCi, PKCips, PKCt, PKCz,PKD1, PKD2, PKD3, PKG1, PKG2, PKN1, PKN2, PKN3, PKR, PLK1, PLK1ps1,PLK1ps2, PLK2, PLK3, PLK4, PRKX, PRKXps, PRKY, PRP4, PRP4ps, PRPK,PSKH1, PSKHlps, PSKH2, PYK2, QIK, QSK, RAF1, RAF1ps, RET, RHOK, RIPK1,RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2, ROS, RSK1, RSK12,RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1, RSKL2, RYK, RYKps, SAKps,SBK, SCYL1, SCYL2, SCYL2ps, SCYL3, SGK, SgK050ps, SgK069, SgK071,SgK085, SgK110, SgK196, SGK2, SgK223, SgK269, SgK288, SGK3, SgK307,SgK384ps, SgK396, SgK424, SgK493, SgK494, SgK495, SgK496, SIK (e.g.,SIK, SIK2), skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, SRC, SRM,SRPK1, SRPK2, SRPK2ps, SSTK, STK33, STK33ps, STLK3, STLK5, STLK6,STLK6ps1, STLK6-rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1,TEC, TESK1, TESK2, TGFbR1, TGFbR2, TIE1, TIE2, TLK1, TLK1ps, TLK2,TLK2ps1, TLK2ps2, TNK1, Trad, Trb1, Trb2, Trb3, Trio, TRKA, TRKB, TRKC,TSSK1, TSSK2, TSSK3, TSSK4, TSSKps1, TSSKps2, TTBK1, TTBK2, TTK, TTN,TXK, TYK2, TYK22, TYRO3, TYRO3ps, ULK1, ULK2, ULK3, ULK4, VACAMKL, VRK1,VRK2, VRK3, VRK3ps, Weel, WeelB, WeelBps, Weelps1, Weelps2, Wnk1, Wnk2,Wnk3, Wnk4, YANK1, YANK2, YANK3, YES, YESps, YSK1, ZAK, ZAP70, ZC1/HGK,ZC2/TNIK, ZC3/MINK, and ZC4/NRK.

The term “CDK” refers to a cyclin-dependent kinase. A CDK binds a cyclin(e.g., Cyclin H), which is a regulatory protein. CDKs phosphorylatetheir substrates at serines and threonines. The consensus sequence forthe phosphorylation site in the amino acid sequence of a CDK substrateis [S/T*]PX[K/R], where S/T* is the phosphorylated serine or threonine,P is proline, X is any amino acid, K is lysine, and R is arginine. CDKsinclude CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10,CDK11, CDK12, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18, CDK19 and CDK20.

CDK7, cyclin-dependent kinase 7, is a CDK, wherein the substrate isCyclin H, MAT1 (e.g., MNAT1), or Cyclin H and MAT1. CDK7 isalternatively referred to as CAK1, HCAK, MO15, STK1, CDKN7, and p39MO15.Non-limiting examples of the nucleotide and protein sequences for humanCDK7 are described in GenBank Accession Number NP_001790, incorporatedherein by reference. The amino acid sequence of this CDK7 is as follows:

MALDVKSRAKRYEKLDFLGEGQFATVYKARDKNTNQIVAIKKIKLGHRSEAKDGINRTALREIKLLQELSHPNIIGLLDAFGHKSNISLVFDFMETDLEVIIKDNSLVLTPSHIKAYMLMTLQGLEYLHQHWILHRDLKPNNLLLDENGVLKLADFGLAKSFGSPNRAYTHQWTRWYRAPELLFGARMYGVGVDMWAVGCILAELLLRVPFLPGDSDLDQLTRIFETLGTPTEEQWPDMCSLPDYVTFKSFPGIPLHHIFSAAGDDLLDLIQGLFLFNPCARITATQALKMKYFSNRPGPTPGCQLPRPNCPVETLKEQSNPALAIKRKRTEALEQGGLPKKLIF

CDK12, cyclin-dependent kinase 12, is a CDK, wherein the substrate isCyclin K or Flavopiridol. CDK12 is alternatively referred to asCdc2-related kinase, CDC2-related protein kinase 7, Cell division cycle2-related protein kinase 7, Cell division protein kinase 12, CRK7, CRKR,CRKRS, cyclin-dependent kinase 12, or KIAA0904. Non-limiting examples ofthe nucleotide and protein sequences for human CDK12 are described inUniprot Number Q9NYV4, which is incorporated herein by reference. Theamino acid sequence of this CDK12 is as follows:

MPNSERHGGKKDGSGGASGTLQPSSGGGSSNSRERHRLVSKHKRHKSKHSKDMGLVTPEAASLGTVIKPLVEYDDISSDSDTFSDDMAFKLDRRENDERRGSDRSDRLHKHRHHQHRRSRDLLKAKQTEKEKSQEVSSKSGSMKDRISGSSKRSNEETDDYGKAQVAKSSSKESRSSKLHKEKTRKERELKSGHKDRSKSHRKRETPKSYKTVDSPKRRSRSPHRKWSDSSKQDDSPSGASYGQDYDLSPSRSHTSSNYDSYKKSPGSTSRRQSVSPPYKEPSAYQSSTRSPSPYSRRQRSVSPYSRRRSSSYERSGSYSGRSPSPYGRRRSSSPFLSKRSLSRSPLPSRKSMKSRSRSPAYSRHSSSHSKKKRSSSRSRHSSISPVRLPLNSSLGAELSRKKKERAAAAAAAKMDGKESKGSPVFLPRKENSSVEAKDSGLESKKLPRSVKLEKSAPDTELVNVTHLNTEVKNSSDTGKVKLDENSEKHLVKDLKAQGTRDSKPIALKEEIVTPKETETSEKETPPPLPTIASPPPPLPTTTPPPQTPPLPPLPPIPALPQQPPLPPSQPAFSQVPASSTSTLPPSTHSKTSAVSSQANSQPPVQVSVKTQVSVTAAIPHLKTSTLPPLPLPPLLPGDDDMDSPKETLPSKPVKKEKEQRTRHLLTDLPLPPELPGGDLSPPDSPEPKAITPPQQPYKKRPKICCPRYGERRQTESDWGKRCVDKFDIIGIIGEGTYGQVYKAKDKDTGELVALKKVRLDNEKEGFPITAIREIKILRQLIHRSWNMKEIVTDKQDALDFKKDKGAFYLVFEYMDHDLMGLLESGLVHFSEDHIKSFMKQLMEGLEYCHKKNFLHRDIKCSNILLNNSGQIKLADFGLARLYNSEESRPYTNKVITLWYRPPELLLGEERYTPAIDVWSCGCILGELFTKKPIFQANLELAQLELISRLCGSPCPAVWPDVIKLPYFNTMKPKKQYRRRLREEFSFIPSAALDLLDHMLTLDPSKRCTAEQTLQSDFLKDVELSKMAPPDLPHWQDCHELWSKKRRRQRQSGVWEEPPPSKTSRKETTSGTSTEPVKNSSPAPPQPAPGKVESGAGDAIGLADITQQLNQSELAVLLNLLQSQTDLSIPQMAQLLNIHSNPEMQQQLEALNQSISALTEATSQQQDSETMAPEESLKEAPSAPVILPSAEQTTLEASSTPADMQNILAVLLSQLMKTQEPAGSLEENNSDKNSGPQGPRRTPTMPQEEAAACPPHILPPEKRPPEPPGPPPPPPPPPLVEGDLSSAPQELNPAVTAALLQLLSQPEAEPPGHLPHEHQALRPMEYSTRPRPNRTYGNTDGPETGFSAIDTDERNSGPALTESLVQTLVKNRTFSGSLSHLGESSSYQGTGSVQFPGDQDLRFARVPLALHPVVGQPFLKAEGSSNSVVHAETKLQNYGELGPGTTGASSSGAGLHWGGPTQ SSAYGKLYRGPTRVPPRGGRGRGVPY

CDK13, cyclin-dependent kinase 13, is a CDK, wherein the relevant cyclinis cyclin K and a reference inhibitor is the pan-CDK inhibitorFlavopiridol and the c-terminal domain (CTD) of RNA-polymerase II is aphysiological substrate. CDK13 is alternatively referred to as CHED;CDC2L; CDC2L5; or hCDK13. Non-limiting examples of the nucleotide andprotein sequences for human CDK12 are described in GenBank AccessionNumber M80629, which is incorporated herein by reference. The amino acidsequence of this CDK13 is as follows:

MPSSSDTALGGGGGLSWAEKKLEERRKRRRFLSPQQPPLLLPLLQPQLLQPPPPPPPLLFLAAPGTAAAAAAAAAASSSCFSPGPPLEVKRLARGKRRAGGRQKRRRGPRAGQEAEKRRVFSLPQPQQDGGGGASSGGGVTPLVEYEDVSSQSEQGLLLGGASAATAATAAGGTGGSGGSPASSSGTQRRGEGSERRPRRDRRSSSGRSKERHREHRRRDGQRGGSEASKSRSRHSHSGEERAEVAKSGSSSSSGGRRKSASATSSSSSSRKDRDSKAHRSRTKSSKEPPSAYKEPPKAYREDKTEPKAYRRRRSLSPLGGRDDSPVSHRASQSLRSRKSPSPAGGGSSPYSRRLPRSPSPYSRRRSPSYSRHSSYERGGDVSPSPYSSSSWRRSRSPYSPVLRRSGKSRSRSPYSSRHSRSRSRHRLSRSRSRHSSISPSTLTLKSSLAAELNKNKKARAAEAARAAEAAKAAEATKAAEAAAKAAKASNTSTPTKGNTETSASASQTNHVKDVKKIKIEHAPSPSSGGTLKNDKAKTKPPLQVTKVENNLIVDKATKKAVIVGKESKSAATKEESVSLKEKTKPLTPSIGAKEKEQHVALVTSTLPPLPLPPMLPEDKEADSLRGNISVKAVKKEVEKKLRCLLADLPLPPELPGGDDLSKSPEEKKTATQLHSKRRPKICGPRYGETKEKDIDWGKRCVDKFDIIGIIGEGTYGQVYKARDKDTGEMVALKKVRLDNEKEGFPITAIREIKILRQLTHQSIINMKEIVTDKEDALDFKKDKGAFYLVFEYMDHDLMGLLESGLVHFNENHIKSFMRQLMEGLDYCHKKNFLHRDIKCSNILLNNRGQIKLADFGLARLYSSEESRPYTNKVITLWYRPPELLLGEERYTPAIDVWSCGCILGELFTKKPIFQANQELAQLELISRICGSPCPAVWPDVIKLPYFNTMKPKKQYRRKLREEFVFIPAAALDLFDYMLALDPSKRCTAEQALQCEFLRDVEPSKMPPPDLPLWQDCHELWSKKRRRQKQMGMTDDVSTIKAPRKDLSLGLDDSRTNTPQGVLPSSQLKSQGSSNVAPVKTGPGQHLNHSELAILLNLLQSKTSVNMADFVQVLNIKVNSETQQQLNKINLPAGILATGEKQTDPSTPQQESSKPLGGIQPSSQTIQPKVETDAAQAAVQSAFAVLLTQLIKAQQSKQKDVLLEERENGSGHEASLQLRPPPEPSTPVSGQDDLIQHQDMRILELTPEPDRPRILPPDQRPPEPPEPPPVTEEDLDYRTENQHVPTTSSSLTDPHAGVKAALLQLLAQHQPQDDPKREGGIDYQAGDTYVSTSDYKDNFGSSSFSSAPYVSNDGLGSSSAPPLERRSFIGNSDIQSLDNYSTASSHSGGPPQPSAFSESFPSSVAGYGDIYLNAGPMLFSGDKDHRFEYSHGPIAVLANSSDPSTGPESTHPLPAKMHNYNYGGNLQENPSGPSLMHGQTWTSPAQGPGYSQGYRGHISTSTGRG RGRGLPY

The term “PIP kinases”, also known as “PIPKs,” refers tophosphatidylinositol phosphate kinases orphosphatidylinositol-5-phosphate 4-kinases, a class of enzymes thatcatalyzes the chemical reaction: ATP+1-phosphatidyl-1D-myo-inositol4-phosphate≈ADP +1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate. PIPkinases are divided into two classes, type I and type II. The type I andtype II PIP kinases are 35% identical at the kinase domain. Theirsequences are significantly divergent for a stretch of about 25 aminoacids in the region of the kinase domain that corresponds to theactivation loop of protein kinases. There are three isoforms of type IIPIP4-kinase in mammalian cells, namely α (PIP4K2A), β (PIP4K2B), and γ(PIP4K2C) isoforms (Liu et al., Nat. Rev. Drug. Discov., 2009, 8(8):627-644). At the protein level, the α and β isoforms are 83% identicaland the γ isoform is about 60% identical to either one of them. Allisoforms are ubiquitously expressed, but the α isoform is foundpredominantly in brain and platelets, the β isoform in brain and muscle,and the γ isoform in brain and kidney. Although the type II PIP4-kinaseisoforms are ubiquitously expressed, changes in protein levels may playa role in the regulation of their cellular function. The type IIPIP4-kinase β isoform gene, which localizes to the chromosome 1711-12,was found to be amplified in primary breast cancer samples withHeregulin 2 gene amplifications and in a subset of breast cancer celllines. These gene amplifications resulted in increased proteinexpression, which correlated with increased breast cancer cellproliferation and anchorage-independent growth (Emerling et al., Cell,2013, 155(4): 844-857). In certain embodiments, the PIPK is PI5P4Kα(i.e. PIP4K2A enzyme) encoded by PIP4K2A gene. In certain embodiments,the PIPK is PI5P4Kβ (i.e. PIP4K2B enzyme) encoded by PIP4K2B gene. Incertain embodiments, the PIPK is PI5P4Kγ (i.e. PIP4K2C enzyme) encodedby PIP4K2C gene. As used herein, type II PIP4Ks enzymes are referred asfollows: PI5P4K is interchangeable with PIP4K; PI5P4Kα isinterchangeable with PIP4Kα, PIP4K2A, PIP4K2A enzyme, and PIP4K2Aprotein; PI5P4Kβ is interchangeable with PIP4Kβ, PIP4K2B, PIP4K2Benzyme, and PIP4K2B protein; PI5P4Kγ is interchangeable with PP4Kγ,PIP4K2C, PIP4K2C enzyme, and PIP4K2C protein.

In certain embodiments, the PIP4K2A enzyme is splP48426PI42A_HUMANPhosphatidylinositol 5-phosphate 4-kinase type-2 alpha (OS═Homo sapiens,GN=PIP4K2A, PE=1, and SV=2) and of the following sequence:

MATPGNLGSSVLASKTKTKKKHFVAQKVKLFRASDPLLSVLMWGVNHSINELSHVQIPVMLMPDDFKAYSKIKVDNHLFNKENMPSHFKFKEYCPMVFRNLRERFGIDDQDFQNSLTRSAPLPNDSQARSGARFHTSYDKRYIIKTITSEDVAEMHNILKKYHQYIVECHGITLLPQFLGMYRLNVDGVEIYVIVTRNVFSHRLSVYRKYDLKGSTVAREASDKEKAKELPTLKDNDFINEGQKIYIDDNNKKVFLEKLKKDVEFLAQLKLMDYSLLVGIHDVERAEQEEVECEENDGEEEGESDGTHPVGTPPDSPGNTLNSSPPLAPGEFDPNIDVYGIKCHENSPRKEVYFMAIIDILTHYDAKKKAAHAAKTVKHGAGAEIST VNPEQYSKRFLDFIGHILT

In certain embodiments, the PIP4K2B enzyme is spIP78356PI42B_HUMANPhosphatidylinositol 5-phosphate 4-kinase type-2 beta (OS═Homo sapiens,GN=PIP4K2B, PE=1, and SV=1) and of the following sequence:

MSSNCTSTTAVAVAPLSASKTKTKKKHFVCQKVKLFRASEPILSVLMWGVNHTINELSNVPVPVMLMPDDFKAYSKIKVDNHLFNKENLPSRFKFKEYCPMVFRNLRERFGIDDQDYQNSVTRSAPINSDSQGRCGTRFLTTYDRRFVIKTVSSEDVAEMHNILKKYHQFIVECHGNTLLPQFLGMYRLTVDGVETYMWTRNVFSHRLTVHRKYDLKGSTVAREASDKEKAKDLPTFKDNDFLNEGQKLHVGEESKKNFLEKLKRDVEFLAQLKIMDYSLLVGIHDVDRAEQEEMEVEERAEDEECENDGVGGNLLCSYGTPPDSPGNLLSFPRFFGPGEFDPSVDVYAMKSHESSPKKEVYFMAIIDILTPYDTKKKAAHAAKTVK HGAGAEISTVNPEQYSKRFNEFMSNILT

In certain embodiments, the PIP4K2C enzyme is splQ8TBX81PI42C_HUMANPhosphatidylinositol 5-phosphate 4-kinase type-2 gamma (OS═Homo sapiens,GN=PIP4K2C, PE=1, and SV=3) and of the following sequence:

MASSSVPPATVSAATAGPGPGFGFASKTKKKHFVQQKVKVFRAADPLVGVFLWGVAHSINELSQVPPPVMLLPDDFKASSKIKVNNHLFHRENLPSHFKFKEYCPQVFRNLRDRFGIDDQDYLVSLTRNPPSESEGSDGRFLISYDRTLVIKEVSSEDIADMHSNLSNYHQYIVKCHGNTLLPQFLGMYRVSVDNEDSYMLVMRNMFSHRLPVHRKYDLKGSLVSREASDKEKVKELPTLKDMDFLNKNQKVYIGEEEKKIFLEKLKRDVEFLVQLKIMDYSLLLGIHDIIRGSEPEEEAPVREDESEVDGDCSLTGPPALVGSYGTSPEGIGGYIHSHRPLGPGEFESFIDVYAIRSAEGAPQKEVYFMGLIDILTQYDAKKKAAHAAKTVKHGAGAEISTVHPEQYAKRFLDFITNIFA

In certain embodiments, the PIP4K2A gene of Gene ID: 5305 and HGNC:8997and has the cDNA sequence as follows:

ATGGCGACCCCCGGCAACCTAGGGTCCTCTGTCCTGGCGAGCAAGACCAAGACCAAGAAGAAGCACTTCGTAGCGCAGAAAGTGAAGCTGTTTCGGGCCAGCGACCCGCTGCTCAGCGTCCTCATGTGGGGGGTAAACCACTCGATCAATGAACTGAGCCATGTTCAAATCCCTGTTATGTTGATGCCAGATGACTTCAAAGCCTATTCAAAAATAAAGGTGGACAATCACCTTTTTAACAAAGAAAACATGCCGAGCCATTTCAAGTTTAAGGAATACTGCCCGATGGTCTTCCGTAACCTGCGGGAGAGGTTTGGAATTGATGATCAAGATTTCCAGAATTCCCTGACCAGGAGCGCACCCCTCCCCAACGACTCCCAGGCCCGCAGTGGAGCTCGTTTTCACACTTCCTACGACAAAAGATACATCATCAAGACTATTACCAGTGAAGACGTGGCCGAAATGCACAACATCCTGAAGAAATACCACCAGTACATAGTGGAATGTCATGGGATCACCCTTCTTCCCCAGTTCTTGGGCATGTACCGGCTTAATGTTGATGGAGTTGAAATATATGTGATAGTTACAAGAAATGTATTCAGCCACCGTTTGTCTGTGTATAGGAAATACGACTTAAAGGGCTCTACAGTGGCTAGAGAAGCTAGTGACAAAGAAAAGGCCAAAGAACTGCCAACTCTGAAAGATAATGATTTCATTAATGAGGGCCAAAAGATTTATATTGATGACAACAACAAGAAGGTCTTCCTGGAAAAACTAAAAAAGGATGTTGAGTTTCTGGCCCAGCTGAAGCTCATGGACTACAGTCTGCTGGTGGGAATTCATGATGTGGAGAGAGCCGAACAGGAGGAAGTGGAGTGTGAGGAGAACGATGGGGAGGAGGAGGGCGAGAGCGATGGCACCCACCCGGTGGGAACCCCCCCAGATAGCCCCGGGAATACACTGAACAGCTCACCACCCCTGGCTCCCGGGGAGTTCGATCCGAACATCGACGTCTATGGAATTAAGTGCCATGAAAACTCGCCTAGGAAGGAGGTGTACTTCATGGCAATTATTGACATCCTTACTCATTATGATGCAAAAAAGAAAGCTGCCCATGCTGCAAAAACTGTTAAACATGGCGCTGGCGCGGAGATCTCCACCGTGAACCCAGAACAGTATTCAAAGCGCTTTTTGGACTTTATTGGCCACATCTTGACGTAA

In certain embodiments, the PIP4K2B gene of Gene ID: 8396 and HGNC:8998,and has the cDNA sequence as follows:

ATGTCGTCCAACTGCACCAGCACCACGGCGGTGGCGGTGGCGCCGCTCAGCGCCAGCAAGACCAAGACCAAGAAGAAGCATTTCGTGTGCCAGAAAGTGAAGCTATTCCGGGCCAGCGAGCCGATCCTCAGCGTCCTGATGTGGGGGGTGAACCACACGATCAATGAGCTGAGCAATGTTCCTGTTCCTGTCATGCTAATGCCAGATGACTTCAAAGCCTACAGCAAGATCAAGGTGGACAATCATCTCTTCAATAAGGAGAACCTGCCCAGCCGCTTTAAGTTTAAGGAGTATTGCCCCATGGTGTTCCGAAACCTTCGGGAGAGGTTTGGAATTGATGATCAGGATTACCAGAATTCAGTGACGCGCAGCGCCCCCATCAACAGTGACAGCCAGGGTCGGTGTGGCACGCGTTTCCTCACCACCTACGACCGGCGCTTTGTCATCAAGACTGTGTCCAGCGAGGACGTGGCGGAGATGCACAACATCTTAAAGAAATACCACCAGTTTATAGTGGAGTGTCATGGCAACACGCTTTTGCCACAGTTCCTGGGCATGTACCGCCTGACCGTGGATGGTGTGGAAACCTACATGGTGGTTACCAGGAACGTGTTCAGCCATCGGCTCACTGTGCATCGCAAGTATGACCTCAAGGGTTCTACGGTTGCCAGAGAAGCGAGCGACAAGGAGAAGGCCAAGGACTTGCCAACATTCAAAGACAATGACTTCCTCAATGAAGGGCAGAAGCTGCATGTGGGAGAGGAGAGTAAAAAGAACTTCCTGGAGAAACTGAAGCGGGACGTTGAGTTCTTGGCACAGCTGAAGATCATGGACTACAGCCTGCTGGTGGGCATCCACGACGTGGACCGGGCAGAGCAGGAGGAGATGGAGGTGGAGGAGCGGGCAGAGGACGAGGAGTGTGAGAATGATGGGGTGGGTGGCAACCTACTCTGCTCCTATGGCACACCTCCGGACAGCCCTGGCAACCTCCTCAGCTTTCCTCGGTTCTTTGGTCCTGGGGAATTCGACCCCTCTGTTGACGTCTATGCCATGAAAAGCCATGAAAGTTCCCCCAAGAAGGAGGTGTATTTCATGGCCATCATTGATATCCTCACGCCATACGATACAAAGAAGAAAGCTGCACATGCTGCCAAAACGGTGAAACACGGGGCAGGGGCCGAGATCTCGACTGTGAACCCTGAGCAGTACTCCAAACGCTTCAACGAGTTTATGTCCAACATCCTGACGTAG

In certain embodiments, the PIP4K2C gene of Gene ID: 79837 andHGNC:23786, and has the cDNA sequence as follows:

ATGGCGTCCTCCTCGGTCCCACCAGCCACGGTATCGGCGGCGACAGCAGGCCCCGGCCCAGGTTTCGGCTTCGCCTCCAAGACCAAGAAGAAGCATTTCGTGCAGCAGAAGGTGAAGGTGTTCCGGGCGGCCGACCCGCTGGTGGGTGTGTTCCTGTGGGGCGTAGCCCACTCGATCAATGAGCTCAGCCAGGTGCCTCCCCCGGTGATGCTGCTGCCAGATGACTTTAAGGCCAGCTCCAAGATCAAGGTCAACAATCACCTTTTCCACAGGGAAAATCTGCCCAGTCATTTCAAGTTCAAGGAGTATTGTCCCCAGGTCTTCAGGAACCTCCGTGATCGATTTGGCATTGATGACCAAGATTACTTGGTGTCCCTTACCCGAAACCCCCCCAGCGAAAGTGAAGGCAGTGATGGTCGCTTCCTTATCTCCTACGATCGGACTCTGGTCATCAAAGAAGTATCCAGTGAGGACATTGCTGACATGCATAGCAACCTCTCCAACTATCACCAGTACATTGTGAAGTGCCATGGCAACACGCTTCTGCCCCAGTTCCTGGGGATGTACCGAGTCAGTGTGGACAACGAAGACAGCTACATGCTTGTGATGCGCAATATGTTTAGCCACCGTCTTCCTGTGCACAGGAAGTATGACCTCAAGGGTTCCCTAGTGTCCCGGGAAGCCAGCGATAAGGAAAAGGTTAAAGAATTGCCCACCCTTAAGGATATGGACTTTCTCAACAAGAACCAGAAAGTATATATTGGTGAAGAGGAGAAGAAAATATTTCTGGAGAAGCTGAAGAGAGATGTGGAGTTTCTAGTGCAGCTGAAGATCATGGACTACAGCCTTCTGCTAGGCATCCACGACATCATTCGGGGCTCTGAACCAGAGGAGGAAGCGCCCGTGCGGGAGGATGAGTCAGAGGTGGATGGGGACTGCAGCCTGACTGGACCTCCTGCTCTGGTGGGCTCCTATGGCACCTCCCCAGAGGGTATCGGAGGCTACATCCATTCCCATCGGCCCCTGGGCCCAGGAGAGTTTGAGTCCTTCATTGATGTCTATGCCATCCGGAGTGCTGAAGGAGCCCCCCAGAAGGAGGTCTACTTCATGGGCCTCATTGATATCCTTACACAGTATGATGCTAAGAAGAAAGCAGCTCATGCAGCCAAAACTGTCAAGCATGGGGCTGGGGCAGAGATCTCTACTGTCCATCCGGAGCAGTATGCTAAGCGATTCCTGGATTTTATTACCAACATCTTT GCCTAA

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows that loss of PIP4K2α/β restricts tumor death after p53deletion. Kaplan-Meier plot analysis was conducted for tumor freesurvival after p53 deletion. 15 TP53^(−/−) PIP4K2A^(+/+) PIP4K2B^(+/+)and 20 TP53^(−/−) PIP4K2A^(−/−) PIP4K2B^(+/−) mice were tested. *p<0.05with two-tailed Student's t test. TP53^(−/−) PIP4K2A^(−/−) PIP4K2B^(+/−)mice had a great increase of tumor free survival compared to TP53^(−/−)PIP4K2A^(+/+) PIP4K2B^(+/+) mice. (Emerling et al., Cell, 2013,155(4):844-57).

FIG. 2 shows an exemplary synthesis of compound 8.

FIGS. 3A to 3D show inhibition of PI5P4Kα/β by compound 8. FIG. 3A showscompound 8 inhibited the kinase activity of both PIP4K2A and PIP4K2B.Radiometric kinase assay was performed using C³²P-ATP and PI5P. Theradiolabeled product, PI(_(4,5))P2 was measured after the separation bythin layer chromatography. FIG. 3B shows compound 8 inhibited theproliferation of TP53 mutant BT474 cells at 1 μM. FIG. 3C shows compound8 stayed effective in inhibiting the proliferation of TP53 mutant BT474cells after 6 hours of treatment and washout. FIG. 3D shows compound 8didn't inhibit TP53 wild type MCF7 cells even at 5 μM. “uM” denotes“μM”.

FIG. 4A and FIG. 4B show LC-MS evaluation of PIP4K2B-Negative-Controlfor 2 hours at room temperature in DMSO.

FIG. 5A and FIG. 5B show LC-MS evaluation of PIP4K2B labeling byCompound 8 for 2 hours at room temperature in DMSO (100% labeling).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

Recent studies have shown that lipid kinases play an essential role ininhibiting cancer cell growth when the TP53 function is absent.Depletion of two lipid kinases, PIP4K2A and PIP4K2B, selectivelyinhibited the proliferation of TP53 mutant breast cancer cell line(BT474 cells) while cells that were wild-type for TP53 were unaffected(Emerling et al., Cell, 2013, 155: 844-857). Further research has shownthat mice expressing one allele of PIP4K2B and homozygous deletion ofPIP4K2A and TP53 are viable and exhibit a dramatic reduction in cancersand extended lifespan compared to their littermates that were TP53deleted with wild type PIP4K2A. Therefore, small molecule inhibitors oflipid kinases may hold promise as a therapeutic agent for treatingproliferative diseases.

The present invention provides compounds, which inhibit the activity ofa kinase, for the prevention and/or treatment of a proliferative diseaseof a subject. In certain embodiments, the inventive compounds inhibitthe activity of a lipid kinase, such as PIP4K. The present inventionfurther provides methods of using the compounds described herein, e.g.,as biological probes to study the modulation of the activity of a kinase(e.g., a lipid kinase such as PIP4K), and as therapeutics, e.g., in theprevention and/or treatment of diseases associated with theoverexpression and/or aberrant activity of the kinase (e.g., a lipidkinase such as PIP4K). In certain embodiments, the disease being treatedand/or prevented is a proliferative disease. Exemplary proliferativediseases include, but are not limited to, cancers (e.g., lung cancer,breast cancer, leukemia, melanoma, multiple myeloma), benign neoplasms,angiogenesis, inflammatory diseases, autoinflammatory diseases, andautoimmune diseases. In certain embodiments, the cancer is associatedwith the overexpression and/or aberrant activity of a kinase (e.g., alipid kinase such as PIP4K).

Compounds

In one aspect of the present invention, provided are compounds ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is a substituted or unsubstituted heteroaryl ring;

each instance of R^(A) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;

each instance of R^(a) is independently hydrogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(a) are joined to form a substituted or unsubstituted, heterocyclicring, or substituted or unsubstituted, heteroaryl ring;

-   -   k is 0, 1, 2, 3, 4, 5, or 6;

L is a bond, —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or—NR^(c)—;

each instance of R^(b) is independently hydrogen, halogen, orsubstituted or unsubstituted C₁₋₆ alkyl;

each instance of R^(c) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group;

R^(B1) is hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂, —SR^(a),—CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), —C(═NR^(a))N(R^(a))₂,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂, —OC(═O)R^(a), —OC(═O)OR^(a),or —OC(═O)N(R^(a))₂;

R^(B2) is hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂, —SR^(a),—CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), —C(═NR^(a))N(R^(a))₂,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂, —OC(═O)R^(a), —OC(═O)OR^(a),or —OC(═O)N(R^(a))₂;

X is —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR^(c)—,—C(R^(b))₂C(R^(b))₂—, —C(R^(b))₂C(═O)—, —C(═O)C(R^(b))₂—,(E)-CR^(b)═CR^(b)—, (Z)—CR^(b)═CR^(b)—, —C≡C—, —OC(═O)—, —C(═O)O—,—SC(═O)—, —C(═O)S—, —NR^(c)C(═O)—, —C(═O)NR^(c)—, —OC(R^(b))₂—,—C(R^(b))₂O—, —SC(R^(b))₂—, —C(R^(b))₂S—, —NR^(c)C(R^(b))₂—,—C(R^(b))₂NR^(c)—, —S(═O)O—, —OS(═O)—, —S(═O)NR^(c)—, —NR^(c)S(═O)—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(c)—, or —NR^(c)S(═O)₂—;

Ring C is a substituted or unsubstituted phenyl ring, substituted orunsubstituted, monocyclic carbocyclic ring, substituted orunsubstituted, monocyclic heterocyclic ring, or substituted orunsubstituted, monocyclic heteroaryl ring;

Ring D is a substituted or unsubstituted phenyl ring, substituted orunsubstituted, monocyclic carbocyclic ring, or substituted orunsubstituted, monocyclic heterocyclic ring;

provided that at least one of Ring C and Ring D is a substituted orunsubstituted phenyl ring;

each instance of R^(C) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;

-   -   n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

L² is —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR^(c)—,—C(R^(b))₂C(R^(b))₂—, —C(R^(b))₂C(═O)—, —C(═O)C(R^(b))₂—,(E)-CR^(b)═CR^(b)—, (Z)—CR^(b)═CR^(b)—, —C≡C—, —OC(═O)—, —C(═O)O—,—SC(═O)—, —C(═O)S—, —NR^(c)C(═O)—, —C(═O)NR^(c)—, —OC(R^(b))₂—,—C(R^(b))₂O—, —SC(R^(b))₂—, —C(R^(b))₂S—, —NR^(c)C(R^(b))₂—,—C(R^(b))₂NR^(c)—, —S(═O)O—, —OS(═O)—, —S(═O)NR^(c)—, —NR^(c)S(═O)—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(c)—, —NR^(c)S(═O)₂—, —OC(═O)O—,—NR^(c)C(═O)O—, —OC(═O)NR^(c)—, —NR^(c)C(═O)NR^(c)—,—C(R^(b))₂C(═O)C(R^(b))₂—, —OC(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)O—,—NR^(c)C(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)NR^(c)—, or a substituted orunsubstituted C₁₋₄ hydrocarbon chain, optionally wherein one or morecarbon units of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR—;

each instance of R^(D) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

R^(E) is of the formula:

L³ is —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR^(c)—,—C(R^(b))₂C(R^(b))₂—, —C(R^(b))₂C(═O)—, —C(═O)C(R^(b))₂—,(E)-CR^(b)═CR^(b)—, (Z)—CR^(b)═CR^(b)—, —C≡C—, —OC(═O)—, —C(═O)O—,—SC(═O)—, —C(═O)S—, —NR^(c)C(═O)—, —C(═O)NR^(c)—, —OC(R^(b))₂—,—C(R^(b))₂O—, —SC(R^(b))₂—, —C(R^(b))₂S—, —NR^(c)C(R^(b))₂—,—C(R^(b))₂NR^(c)—, —S(═O)O—, —OS(═O)—, —S(═O)NR^(c)—, —NR^(c)S(═O)—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(c)—, —NR^(c)S(═O)₂—, —OC(═O)O—,—NR^(c)C(═O)O—, —OC(═O)NR^(c)—, —NR^(c)C(═O)NR^(c)—,—C(R^(b))₂C(═O)C(R^(b))₂—, —OC(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)O—,—NR^(c)C(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)NR^(c)—, or a substituted orunsubstituted C₁₋₄ hydrocarbon chain, optionally wherein one or morecarbon units of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR^(c)—;

L⁴ is a bond or substituted or unsubstituted C₁₋₆ hydrocarbon chain;

each of R^(E1), R^(E2), and R^(E3) is independently hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —CH₂R^(a), —CH₂N(R^(a))₂, —CH₂SR^(a), —OR, —N(R^(a))₂,—SR^(a), or —Si(R^(a))₃; or R^(E1) and R^(E3), or R^(E2) and R^(E3), orR^(E1) and R^(E2) are joined to form a substituted or unsubstituted,carbocyclic ring, or substituted or unsubstituted, heterocyclic ring;

R^(E4) is a leaving group;

R^(E5) is halogen;

R^(E6) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group;

each instance of Y is independently O, S, or NR^(c);

a is 1 or 2; and

each instance of z is independently 0, 1, 2, 3, 4, 5, or 6.

In certain embodiments, the compound described herein is of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is a substituted or unsubstituted heteroaryl ring;

each instance of R^(A) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;

each instance of R^(a) is independently hydrogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(a) are joined to form a substituted or unsubstituted, heterocyclicring, or substituted or unsubstituted, heteroaryl ring;

-   -   k is 0, 1, 2, 3, 4, 5, or 6;

L¹ is a bond, —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or—NR^(c)—;

each instance of R^(b) is independently hydrogen, halogen, orsubstituted or unsubstituted C₁₋₆ alkyl;

each instance of R^(c) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group;

R^(B1) is hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂, —SR^(a),—CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), —C(═NR^(a))N(R^(a))₂,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂, —OC(═O)R^(a), —OC(═O)OR^(a),or —OC(═O)N(R^(a))₂;

R^(B2) is hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂, —SR^(a),—CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), —C(═NR^(a))N(R^(a))₂,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂, —OC(═O)R^(a), —OC(═O)OR^(a),or —OC(═O)N(R^(a))₂;

X is —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR^(c)—,—C(R^(b))₂C(R^(b))₂—, —C(R^(b))₂C(═O)—, —C(═O)C(R^(b))₂—,(E)-CR^(b)═CR^(b)—, (Z)—CR^(b)═CR^(b)—, —C≡C—, —OC(═O)—, —C(═O)O—,—SC(═O)—, —C(═O)S—, —NR^(c)C(═O)—, —C(═O)NR^(c)—, —OC(R^(b))₂—,—C(R^(b))₂O—, —SC(R^(b))₂—, —C(R^(b))₂S—, —NR^(c)C(R^(b))₂—,—C(R^(b))₂NR^(c)—, —S(═O)O—, —OS(═O)—, —S(═O)NR^(c)—, —NR^(c)S(═O)—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(c)—, or —NR^(c)S(═O)₂—;

Ring C is a substituted or unsubstituted phenyl ring, substituted orunsubstituted, monocyclic carbocyclic ring, or substituted orunsubstituted, monocyclic heterocyclic ring;

Ring D is a substituted or unsubstituted phenyl ring, substituted orunsubstituted, monocyclic carbocyclic ring, or substituted orunsubstituted, monocyclic heterocyclic ring;

provided that at least one of Ring C and Ring D is a substituted orunsubstituted phenyl ring;

each instance of R^(C) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

L² is —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR^(c)—,—C(R^(b))₂C(R^(b))₂—, —C(R^(b))₂C(═O)—, —C(═O)C(R^(b))₂—,(E)-CR^(b)═CR^(b)—, (Z)—CR^(b)═CR^(b)—, —C≡C—, —OC(═O)—, —C(═O)O—,—SC(═O)—, —C(═O)S—, —NR^(c)C(═O)—, —C(═O)NR^(c)—, —OC(R^(b))₂—,—C(R^(b))₂O—, —SC(R^(b))₂—, —C(R^(b))₂S—, —NR^(c)C(R^(b))₂—,—C(R^(b))₂NR^(c)—, —S(═O)O—, —OS(═O)—, —S(═O)NR^(c)—, —NR^(c)S(═O)—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(c)—, —NR^(c)S(═O)₂—, —OC(═O)O—,—NR^(c)C(═O)O—, —OC(═O)NR^(c)—, —NR^(c)C(═O)NR^(c)—,—C(R^(b))₂C(═O)C(R^(b))₂—, —OC(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)O—,—NR^(c)C(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)NR^(c)—, or a substituted orunsubstituted C₁₋₄ hydrocarbon chain, optionally wherein one or morecarbon units of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR^(c)—;

each instance of R^(D) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

R^(E) is of the formula:

L³ is —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR^(c)—,—C(R^(b))₂C(R^(b))₂—, —C(R^(b))₂C(═O)—, —C(═O)C(R^(b))₂—,(E)-CR^(b)═CR^(b)—, (Z)—CR^(b)═CR^(b)—, —C≡C—, —OC(═O)—, —C(═O)O—,—SC(═O)—, —C(═O)S—, —NR^(c)C(═O)—, —C(═O)NR^(c)—, —OC(R^(b))₂—,—C(R^(b))₂O—, —SC(R^(b))₂—, —C(R^(b))₂S—, —NR^(c)C(R^(b))₂—,—C(R^(b))₂NR^(c)—, —S(═O)O—, —OS(═O)—, —S(═O)NR^(c)—, —NR^(c)S(═O)—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(c)—, —NR^(c)S(═O)₂—, —OC(═O)O—,—NR^(c)C(═O)O—, —OC(═O)NR^(c)—, —NR^(c)C(═O)NR^(c)—,—C(R^(b))₂C(═O)C(R^(b))₂—, —OC(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)O—,—NR^(c)C(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)NR^(c)—, or a substituted orunsubstituted C₁₋₄ hydrocarbon chain, optionally wherein one or morecarbon units of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR^(c)—;

L⁴ is a bond or substituted or unsubstituted C₁₋₆ hydrocarbon chain;

each of R^(E1), R^(E2), and R^(E3) is independently hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —CH₂R^(a), —CH₂N(R^(a))₂, —CH₂SR^(a), —OR, —N(R^(a))₂,—SR, or —Si(R^(a))₃; or R^(E1) and R^(E3), or R^(E2) and R^(E3), orR^(E1) and R^(E2) are joined to form a substituted or unsubstituted,carbocyclic ring, or substituted or unsubstituted, heterocyclic ring;

R^(E4) is a leaving group;

R^(E5) is halogen;

R^(E6) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group;

each instance of Y is independently O, S, or NR;

a is 1 or 2; and

each instance of z is independently 0, 1, 2, 3, 4, 5, or 6.

Compounds of Formula (I) include Ring A attached to Ring B throughlinker L¹. In certain embodiments, Ring A is a substituted orunsubstituted bicyclic heteroaryl ring. In certain embodiments, Ring Ais a substituted or unsubstituted, 9- or 10-membered, bicyclicheteroaryl ring, wherein one, two, three, or four atoms in theheteroaryl ring system are independently oxygen, nitrogen, or sulfur, asvalency permits. In certain embodiments, Ring A is a substituted orunsubstituted bicyclic heteroaryl ring with one nitrogen. In certainembodiments, Ring A is a substituted or unsubstituted bicyclicheteroaryl ring with two nitrogen. In certain embodiments, Ring A is asubstituted or unsubstituted monocyclic heteroaryl ring fused with asubstituted or unsubstituted monocyclic aryl ring. In certainembodiments, Ring A is a substituted or unsubstituted monocyclicheteroaryl ring fused with another substituted or unsubstitutedmonocyclic heteroaryl ring. Ring A may be a substituted or unsubstituted6,5-membered heteroaryl ring or a substituted or unsubstituted5,6-membered heteroaryl ring. In certain embodiments, Ring A is asubstituted or unsubstituted, 5- or 6-membered, monocyclic heteroarylring, wherein one, two, three, or four atoms in the heteroaryl ringsystem are independently oxygen, nitrogen, or sulfur, as valencypermits. In certain embodiments, Ring A is a substituted orunsubstituted monocyclic 5-membered heteroaryl ring fused with asubstituted or unsubstituted monocyclic 6-membered aryl ring. In certainembodiments, Ring A is a substituted or unsubstituted monocyclic5-membered heteroaryl ring fused with a substituted or unsubstitutedmonocyclic 6-membered heteroaryl ring. The point of attachment of Ring Ato Ring B may be at any atom of Ring A, as valency permits. In certainembodiments, Ring A is of Formula (i-1):

In certain embodiments, Ring A is of Formula (i-2):

In certain embodiments, Ring A is of Formula (i-3):

In certain embodiments, Ring A is of Formula (i-4): V (i-4).

In compounds of Formula (I), V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, and V⁹ ofRing A may each independently be O, S, N, NR^(A1), C, or CR^(A2), asvalency permits. In certain embodiments, V¹ is O, S, N or NR^(A1). Incertain embodiments, V¹ is N or NR^(A1). In certain embodiments, Ring Ais of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, only one of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, andV⁹ is selected from the group consisting of O, S, N, and NR^(A1). Incertain embodiments, only one of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, and V⁹is selected from the group consisting of N and NR^(A1). In certainembodiments, V¹ is N or NR^(A1); V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, and V⁹ areeach independently C or CR^(A2); and therefore, Ring A is a substitutedor unsubstituted indole ring. In certain embodiments, Ring A is ofFormula (A-i):

wherein R^(A1), R^(A2), and k are as defined herein. In certainembodiments, Ring A is of Formula (iii-1):

In certain embodiments, Ring A is of Formula (iii-2):

In certain embodiments, Ring A is of Formula (iii-3):

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of Formula (iii-4):

In certain embodiments, Ring A is of Formula (iii-5):

In certain embodiments, Ring A is of Formula (iii-6):

In certain embodiments, Ring A is of Formula (iii-7):

In certain embodiments, only two of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, andV⁹ are each independently selected from the group consisting of O, S, N,and NR^(A1). In certain embodiments, only two of V¹, V², V³, V⁴, V⁵, V⁶,V⁷, V⁸, and V⁹ are each independently selected from the group consistingof N and NR^(A1). In certain embodiments, V¹ is N or NR^(A1); and onlyone of V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, and V⁹ is N or NR^(A1). In certainembodiments, V¹ and V² are each independently N or NR^(A1); V³, V⁴, V⁵,V⁶, V⁷, V⁸, and V⁹ are each independently C or CR^(A2); and therefore,Ring A is a substituted or unsubstituted indazole ring. In certainembodiments, Ring A is of Formula (A-ii):

wherein R^(A1), R^(A2), and k are as defined herein. In certainembodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of Formula (A-iii):

(A-iii), wherein R^(A1), R^(A2), and k are as defined herein. In certainembodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, V and V³ are each independently N or NR^(A1);V², V⁴, V⁵, V⁶, V⁷, V⁸, and V⁹ are each independently C or CR^(A2); andtherefore, Ring A is a substituted or unsubstituted benzimidazole ring.In certain embodiments, Ring A is of Formula (iv-1):

In certain embodiments, Ring A is of Formula (iv-2):

In certain embodiments, Ring A is of Formula (iv-3):

In certain embodiments, Ring A is of Formula (iv-4):

In certain embodiments, Ring A is of Formula (iv-5):

In certain embodiments, Ring A is of Formula (iv-6):

In certain embodiments, V¹ and V⁴ are each independently N or NR^(A1);V², V³, V⁵, V⁶, V⁷, V⁸, and V⁹ are each independently C or CR^(A2); andtherefore, Ring A is a substituted or unsubstituted 4-azaindazole ring.In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, V¹ and V⁵ are each independently N or NR^(A1);V², V³, V⁴, V⁶, V⁷, V⁸, and V⁹ are each independently C or CR^(A2); andtherefore, Ring A is a substituted or unsubstituted 5-azaindazole ring.In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, V¹ and V⁶ are each independently N or NR^(A1);V², V, V⁴, V⁵, V⁷, V⁸, and V⁹ are each independently C or CR^(A2); andtherefore, Ring A is a substituted or unsubstituted 6-azaindole ring. Incertain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, V¹ and V⁷ are each independently N or NR^(A1);V², V³, V⁴, V⁵, V⁶, V⁸, and V⁹ are each independently C or CR^(A2); andtherefore, Ring A is a substituted or unsubstituted 7-azaindole ring. Incertain embodiments, Ring A is of Formula (v-1):

In certain embodiments, Ring A is of Formula (v-2):

In certain embodiments, Ring A is of Formula (v-3):

In certain embodiments, Ring A is of Formula (v-4):

In certain embodiments, Ring A is of Formula (v-5):

In certain embodiments, Ring A is of Formula (v-6):

In certain embodiments, V¹ and V⁸ are each independently N or NR^(A1),V², V³, V⁴, V⁵, V⁶, V⁷, and V⁹ are each independently C or CR^(A2); andtherefore, Ring A is a substituted or unsubstituted 8-azaindole ring. Incertain embodiments, Ring A is of Formula (vi-1):

In certain embodiments, Ring A is of Formula (vi-2):

In certain embodiments, Ring A is of Formula (vi-3):

In certain embodiments, Ring A is of Formula (vi-4):

In certain embodiments, Ring A is of Formula (vi-5):

In certain embodiments, Ring A is of Formula (vi-6):

In certain embodiments, V¹ and V⁹ are each independently N or NR^(A1);V², V, V⁴, V⁵, V⁶, V⁷, and V⁸ are each independently C or CR^(A2); andtherefore, Ring A is a substituted or unsubstituted 9-azaindole ring. Incertain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, only three of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸,and V⁹ are each independently selected from the group consisting of O,S, N, and NR^(A1). In certain embodiments, only three of V¹, V², V³, V⁴,V⁵, V⁶, V⁷, V⁸, and V⁹ are each independently selected from the groupconsisting of N and NR^(A1). In certain embodiments, V¹ is N or NR^(A1);and only two of V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, and V⁹ are eachindependently N or NR^(A1).

In compounds of Formula (I), Ring A may also be a substituted orunsubstituted monocyclic heteroaryl ring. In compounds of Formula (I),Ring A may also be a substituted or unsubstituted 5-membered heteroarylring. In certain embodiments, Ring A is of Formula (i-5):

In compounds of Formula (I), V¹⁰, V¹¹, V¹², V¹³, and V¹⁴ of Ring A mayeach independently be O, S, N, NR^(A1), C, or CR^(A2), as valencypermits. In certain embodiments, only one of V¹⁰, V¹¹, V¹², V¹³, and V¹⁴is selected from the group consisting of O, S, N, and NR^(A1). Incertain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, only two of V¹⁰, V¹¹, V¹², V¹³, and V¹⁴ are eachindependently selected from the group consisting of O, S, N, andNR^(A1). In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of Formula (vii)

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, only three of V¹⁰, V¹¹, V¹², V¹³, and V¹⁴ areeach independently selected from the group consisting of O, S, N, andNR^(A1). In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, only four of V¹⁰, V¹¹, V¹², V¹³, and V¹⁴ areeach independently selected from the group consisting of N and NR^(A1).In certain embodiments, Ring A is of the formula:

In compounds of Formula (I), Ring A may also be a substituted orunsubstituted 6-membered heteroaryl ring. In certain embodiments, Ring Ais of Formula (i-6):

In compounds of Formula (I), V¹⁰, V¹¹, V¹², V¹³, V¹⁴, and V¹⁵ of Ring Amay each independently be N, C, or CR^(A2), as valency permits. Incertain embodiments, only one of V¹⁰, V¹¹, V¹², V¹³, V¹⁴, and V¹⁵ is N.In certain embodiments, Ring A is of Formula (A-v):

wherein R^(A2) and k are as defined herein. In certain embodiments, RingA is of the formula:

In certain embodiments, only two of V¹⁰, V¹¹, V¹², V¹, V¹⁴ and V¹⁵ areN. In certain embodiments, Ring A is of the formula:

In certain embodiments, only three of V¹⁰, V¹¹, V¹², V¹³, V¹⁴ and V¹⁵are N. In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In compounds of Formula (I), Ring A may be substituted with one or moreR^(A) groups when the R^(A) group is attached to a carbon atom. Incertain embodiments, at least one R^(A) is halogen. In certainembodiments, at least one R^(A) is F. In certain embodiments, at leastone R^(A) is Cl. In certain embodiments, at least one R^(A) is Br. Incertain embodiments, at least one R^(A) is I (iodine). In certainembodiments, at least one R^(A) is substituted alkyl. In certainembodiments, at least one R^(A) is unsubstituted alkyl. In certainembodiments, at least one R^(A) is C₁₋₆ alkyl. In certain embodiments,at least one R^(A) is methyl. In certain embodiments, at least one R^(A)is ethyl. In certain embodiments, at least one R^(A) is propyl. Incertain embodiments, at least one R^(A) is substituted alkenyl. Incertain embodiments, at least one R^(A) is unsubstituted alkenyl. Incertain embodiments, at least one R^(A) is vinyl. In certainembodiments, at least one R^(A) is substituted alkynyl. In certainembodiments, at least one R^(A)is unsubstituted alkynyl. In certainembodiments, at least one R^(A) is ethynyl. In certain embodiments, atleast one R^(A) is substituted carbocyclyl. In certain embodiments, atleast one R^(A) is unsubstituted carbocyclyl. In certain embodiments, atleast one R^(A) is substituted heterocyclyl. In certain embodiments, atleast one R^(A) is unsubstituted heterocyclyl. In certain embodiments,at least one R^(A) is substituted aryl. In certain embodiments, at leastone R^(A) is unsubstituted aryl. In certain embodiments, at least oneR^(A) is substituted phenyl. In certain embodiments, at least one R^(A)is unsubstituted phenyl. In certain embodiments, at least one R^(A) issubstituted heteroaryl. In certain embodiments, at least one R^(A) is—OR^(a), wherein R^(a) is as defined herein. In certain embodiments, atleast one R^(A) is —OR^(a), wherein R^(Aa) is hydrogen. In certainembodiments, at least one R^(A) is —OR^(a), wherein R^(a) is hydrogen orsubstituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, atleast one R^(A) is —OR^(a), wherein R^(a) is unsubstituted C₁₋₆ alkyl.In certain embodiments, at least one R^(A) is —OCH₃. In certainembodiments, at least one R^(A) is —N(R^(a))₂, wherein R^(a) is hydrogenor substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, atleast one R^(A) is —NHR^(a). In certain embodiments, at least one R^(A)is —SR^(a).

In compounds of Formula (I), Ring A may be substituted with one or moreR^(A) groups as valency permits. In certain embodiments, k is 0. Incertain embodiments, k is 1. In certain embodiments, k is 2. In certainembodiments, k is 3. In certain embodiments, k is 5. In certainembodiments, k is 6.

In certain embodiments, at least one instance of R^(A1) is H (hydrogen).In certain embodiments, at least one instance of R^(A1) is halogen. Incertain embodiments, at least one instance of R^(A1) is F (fluorine). Incertain embodiments, at least one instance of R^(A1) is Cl (chlorine).In certain embodiments, at least one instance of R^(A1) is Br (bromine).In certain embodiments, at least one instance of R^(A1) is I (iodine).In certain embodiments, at least one instance of R^(A1) is substitutedacyl. In certain embodiments, at least one instance of R^(A1) isunsubstituted acyl. In certain embodiments, at least one instance ofR^(A1) is acetyl. In certain embodiments, at least one instance ofR^(A1) is substituted acetyl. In certain embodiments, at least oneinstance of R^(A1) is substituted alkyl. In certain embodiments, atleast one instance of R^(A1) is unsubstituted alkyl. In certainembodiments, at least one instance of R^(A1) is C₁₋₆ alkyl. In certainembodiments, at least one instance of R^(A1) is methyl. In certainembodiments, at least one instance of R^(A1) is ethyl. In certainembodiments, at least one instance of R^(A1) is propyl. In certainembodiments, at least one instance of R^(A1) is butyl. In certainembodiments, at least one instance of R^(A1) is substituted alkenyl. Incertain embodiments, at least one instance of R^(A1) is unsubstitutedalkenyl. In certain embodiments, at least one instance of R^(A1) isvinyl. In certain embodiments, at least one instance of R^(A1) issubstituted alkynyl. In certain embodiments, at least one instance ofR^(A1) is unsubstituted alkynyl. In certain embodiments, at least oneinstance of R^(A1) is ethynyl. In certain embodiments, at least oneinstance of R^(A1) is substituted carbocyclyl. In certain embodiments,at least one instance of R^(A1) is unsubstituted carbocyclyl. In certainembodiments, at least one instance of R^(A1) is substitutedheterocyclyl. In certain embodiments, at least one instance of R^(A1) isunsubstituted heterocyclyl. In certain embodiments, at least oneinstance of R^(A1) is substituted aryl. In certain embodiments, at leastone instance of R^(A1) is unsubstituted aryl. In certain embodiments, atleast one instance of R^(A1) is substituted phenyl. In certainembodiments, at least one instance of R^(A1) is unsubstituted phenyl. Incertain embodiments, at least one instance of R^(A1) is substitutedheteroaryl. In certain embodiments, at least one instance of R^(A1) isunsubstituted heteroaryl. In certain embodiments, at least one instanceof R^(A1) is substituted pyridyl. In certain embodiments, at least oneinstance of R^(A1) is unsubstituted pyridyl. In certain embodiments, atleast one instance of R^(A1) is a nitrogen protecting group. In certainembodiments, at least one instance of R^(A1) is Bn, BOC, Cbz, Fmoc,trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

In certain embodiments, at least one R^(A1) is hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group. In certainembodiments, all instances of R^(A1) are each independently hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.In certain embodiments, all instances of R^(A) are hydrogen.

In certain embodiments, at least one R^(A2) is H. In certainembodiments, at least one R^(A2) is halogen. In certain embodiments, atleast one R^(A2) is F. In certain embodiments, at least one R^(A2) isCl. In certain embodiments, at least one R^(A2) is Br. In certainembodiments, at least one R^(A2) is I (iodine). In certain embodiments,at least one R^(A2) is substituted acyl. In certain embodiments, atleast one R^(A2) is unsubstituted acyl. In certain embodiments, at leastone R^(A2) is acetyl. In certain embodiments, at least one R^(A2) issubstituted acetyl. In certain embodiments, at least one R^(A2) issubstituted alkyl. In certain embodiments, at least one R^(A2) isunsubstituted alkyl. In certain embodiments, at least one R^(A2) is C₁₋₆alkyl. In certain embodiments, at least one R^(A2) is methyl. In certainembodiments, at least one R^(A2) is ethyl. In certain embodiments, atleast one R^(A2) is propyl. In certain embodiments, at least one R^(A2)is butyl. In certain embodiments, at least one R^(A2) is substitutedalkenyl. In certain embodiments, at least one R^(A2) is unsubstitutedalkenyl. In certain embodiments, at least one R^(A2) is vinyl. Incertain embodiments, at least one R^(A2) is substituted alkynyl. Incertain embodiments, at least one R^(A2) is unsubstituted alkynyl. Incertain embodiments, at least one R^(A2) is ethynyl. In certainembodiments, at least one R^(A2) is substituted carbocyclyl. In certainembodiments, at least one R^(A) is unsubstituted carbocyclyl. In certainembodiments, at least one R^(A) is substituted heterocyclyl. In certainembodiments, at least one R^(A2) is unsubstituted heterocyclyl. Incertain embodiments, at least one R^(A2) is substituted aryl. In certainembodiments, at least one R^(A2) is unsubstituted aryl. In certainembodiments, at least one R^(A2) is substituted phenyl. In certainembodiments, at least one R^(A2) is unsubstituted phenyl. In certainembodiments, at least one R^(A2) is substituted heteroaryl. In certainembodiments, at least one R^(A2) is unsubstituted heteroaryl. In certainembodiments, at least one R^(A2) is substituted pyridyl. In certainembodiments, at least one R^(A2) is unsubstituted pyridyl. In certainembodiments, at least one R^(A2) is —OR^(A2a), wherein R^(A2a) is asdefined herein. In certain embodiments, at least one R^(A2) is—OR^(A2a), wherein R^(A2a) is hydrogen. In certain embodiments, at leastone R^(A2) is —OR^(A2a), wherein R^(A2a) is substituted or unsubstitutedC₁₋₆ alkyl. In certain embodiments, at least one R^(A2) is —OR^(A2a),wherein R^(A2a) is unsubstituted C₁₋₆ alkyl. In certain embodiments, atleast one R^(A2) is —OCH₃. In certain embodiments, at least one R^(A2)is —N(R^(A2a))₂. In certain embodiments, at least one R^(A2) is—SR^(A2a). In certain embodiments, all instances of R^(A2) are hydrogen.

In certain embodiments, all R^(A1) and R^(A2) are hydrogen. In certainembodiments, R^(A1) is hydrogen; and at least one R^(A2) is substitutedor unsubstituted alkyl. In certain embodiments, R^(A1) is hydrogen; andat least one R^(A2) is unsubstituted alkyl. In certain embodiments,R^(A1) is hydrogen; and at least one R^(A2) is methyl, ethyl, orn-propyl. In certain embodiments, R^(A1) is hydrogen; and at least oneR^(A2) is-OR^(A2a), wherein R^(A2a) is as defined herein. In certainembodiments, R^(A1) is hydrogen; and at least one R^(A2) is-OR^(A2a),wherein R^(A2)a is substituted or unsubstituted C₁₋₆ alkyl. In certainembodiments, R^(A1) is hydrogen; and at least one R^(A2) is-OR^(A2a),wherein R^(A2a) is unsubstituted C₁₋₆ alkyl. In certain embodiments,R^(A1) is hydrogen; and at least one R^(A2) is-OCH₃.

In certain embodiments, R^(a) is H. In certain embodiments, R^(a) ishalogen. In certain embodiments, R^(a) is F. In certain embodiments,R^(a) is Cl. In certain embodiments, R^(a) is Br. In certainembodiments, R^(a) is I (iodine). In certain embodiments, R^(a) issubstituted C₁₋₆ alkyl. In certain embodiments, R^(a) is unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(a) is methyl. In certainembodiments, R^(a) is ethyl. In certain embodiments, at least one R^(a)is H. In certain embodiments, each R^(a) is H. In certain embodiments,at least one R^(a) is halogen (e.g., F, Cl, Br, or I (iodine)). Incertain embodiments, at least one R^(a) is substituted or unsubstitutedalkyl. In certain embodiments, at least one R^(a) is substituted C₁₋₆alkyl. In certain embodiments, at least one R^(a) is unsubstituted C₁₋₆alkyl. In certain embodiments, at least one R^(a) is Me. In certainembodiments, at least one R^(a) is substituted methyl (e.g., —CF₃ orBn), Et, substituted ethyl (e.g., fluorinated ethyl), Pr, substitutedpropyl (e.g., fluorinated propyl), Bu, or substituted butyl (e.g.,fluorinated butyl). In certain embodiments, at least one R^(a) issubstituted or unsubstituted alkenyl or substituted or unsubstitutedalkynyl. In certain embodiments, at least one R^(a) is substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In certain embodiments, at least one R^(a) is a nitrogenprotecting group when attached to a nitrogen atom, an oxygen protectinggroup when attached to an oxygen atom, or a sulfur protecting group whenattached to a sulfur atom. In certain embodiments, two instances ofR^(a) are joined to form a substituted or unsubstituted, heterocyclicring, or substituted or unsubstituted, heteroaryl ring.

As generally defined herein, R^(B1) is hydrogen, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂, wherein R^(a) is asdefined herein. In certain embodiments, R^(B1) is H. In certainembodiments, R^(B1) is halogen. In certain embodiments, R^(B1) is F. Incertain embodiments, R^(B1) is Cl. In certain embodiments, R^(B1) is Br.In certain embodiments, R^(B1) is I (iodine). In certain embodiments,R^(B1) is substituted alkyl. In certain embodiments, R^(B1) isunsubstituted alkyl. In certain embodiments, R^(B1) is C₁₋₆ alkyl. Incertain embodiments, R^(B1) is methyl. In certain embodiments, R^(B1) isethyl. In certain embodiments, R^(B1) is propyl. In certain embodiments,R^(B1) is butyl. In certain embodiments, R^(B1) is —OR^(B1a), whereinR^(B1a) is hydrogen or substituted or unsubstituted alkyl. In certainembodiments, R^(B1) is —N(R^(B1a))₂, wherein each instance of R^(B1a) isindependently H or substituted or unsubstituted alkyl. In certainembodiments, R^(B1) is —NHR^(B1a), wherein R^(B1a) is independently H orsubstituted or unsubstituted alkyl. In certain embodiments, R^(B1) is—NH₂,

As generally defined herein, R^(B2) is hydrogen, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂, wherein R^(a) is asdefined herein. In certain embodiments, R^(B2) is H. In certainembodiments, R^(B2) is halogen. In certain embodiments, R^(B2) is F. Incertain embodiments, R^(B2) is Cl. In certain embodiments, R^(B2) is Br.In certain embodiments, R^(B2) is I (iodine). In certain embodiments,R^(B2) is substituted alkyl. In certain embodiments, R^(B2) isunsubstituted alkyl. In certain embodiments, R^(B2) is C₁₋₆ alkyl. Incertain embodiments, R^(B2) is methyl. In certain embodiments, R^(B2) isethyl. In certain embodiments, R^(B2) is propyl.

In certain embodiments, R^(B1) and R^(B2) are the same. In certainembodiments, R^(B1) and R^(B2) are different. In certain embodiments,both R^(B1) and R^(B2) are hydrogen. In certain embodiments, R^(B1) ishydrogen and R^(B2) is hydrogen, halogen, substituted or unsubstitutedalkyl, —OR^(a), or —N(R^(a))₂, wherein each instance of R^(a) isindependently hydrogen or substituted or unsubstituted alkyl. In certainembodiments, R^(B1) is hydrogen and R^(B2) is halogen. In certainembodiments, R^(B1) is hydrogen and R^(B2) is substituted orunsubstituted alkyl. In certain embodiments, R^(B1) is hydrogen andR^(B2) is unsubstituted alkyl. In certain embodiments, R^(B1) ishydrogen and R^(B2) is methyl or ethyl. In certain embodiments, R^(B2)is hydrogen and R^(B1) is hydrogen, halogen, substituted orunsubstituted alkyl, —OR^(a), or —N(R^(a))₂, wherein each instance ofR^(a) is independently hydrogen, substituted or unsubstituted alkyl, anoxygen protecting group when attached to oxygen, or a nitrogenprotecting group when attached to nitrogen. In certain embodiments,R^(B2) is hydrogen and R^(B1) is halogen. In certain embodiments, R^(B2)is hydrogen and R^(B1) is substituted or unsubstituted alkyl. In certainembodiments, R^(B2) is hydrogen and R^(B1) is unsubstituted alkyl. Incertain embodiments, R^(B2) is hydrogen and R^(B1) is methyl or ethyl.In certain embodiments, R^(B2) is hydrogen and R^(B1) is —OR^(a),wherein R^(a) is independently hydrogen, substituted or unsubstitutedalkyl, or an oxygen protecting group. In certain embodiments, R^(B2) ishydrogen and R^(B1) is —N(R^(a)), wherein each instance of R^(a) isindependently hydrogen, substituted or unsubstituted alkyl, or anitrogen protecting group.

In compounds of Formula (I), L¹ is a divalent linker moiety connectingRing A and Ring B. L¹ may be a bond, —C(R^(b))₂—, —C(═O)—, —O—, —S—,—S(═O)—, —S(═O)₂—, or —NR^(c)—; wherein R^(b) and R^(c) are as definedherein. In certain embodiments, L¹ is a bond. In certain embodiments, L¹is —O—. In certain embodiments, L¹ is —S—. In certain embodiments, L¹ is—NR^(c)—. In certain embodiments, L¹ is —NH—. In certain embodiments, L¹is —C(R^(b))₂—. In certain embodiments, L¹ is —CH₂—.

In certain embodiments, R^(b) is H. In certain embodiments, R^(b) ishalogen. In certain embodiments, R^(b) is F. In certain embodiments,R^(b) is Cl. In certain embodiments, R^(b) is Br. In certainembodiments, R^(b) is I (iodine). In certain embodiments, R^(b) issubstituted C₁₋₆ alkyl. In certain embodiments, R^(b) is unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(b) is methyl. In certainembodiments, R^(b) is ethyl. In certain embodiments, at least one R^(b)is H. In certain embodiments, each R^(b) is H. In certain embodiments,at least one R^(b) is halogen (e.g., F, Cl, Br, or I (iodine)). Incertain embodiments, at least one R^(b) is substituted C₁₋₆ alkyl. Incertain embodiments, at least one R^(b) is unsubstituted C₁₋₆ alkyl. Incertain embodiments, at least one R^(b) is Me. In certain embodiments,at least one R^(b) is substituted methyl (e.g., —CF₃ or Bn), Et,substituted ethyl (e.g., fluorinated ethyl), Pr, substituted propyl(e.g., fluorinated propyl), Bu, or substituted butyl (e.g., fluorinatedbutyl).

In certain embodiments, R^(c) is H. In certain embodiments, R^(c) issubstituted C₁₋₆ alkyl. In certain embodiments, R^(c) is unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(c) is methyl. In certainembodiments, R^(c) is ethyl. In certain embodiments, R^(c) is a nitrogenprotecting group. In certain embodiments, R^(c) is BOC, acetyl, or Ts.In certain embodiments, at least one R^(c) is H. In certain embodiments,each R^(c) is H. In certain embodiments, at least one R^(c) is halogen(e.g., F, Cl, Br, or I (iodine)). In certain embodiments, at least oneR^(c) is substituted C₁₋₆ alkyl. In certain embodiments, at least oneR^(c) is unsubstituted C₁₋₆ alkyl. In certain embodiments, at least oneR^(c) is Me. In certain embodiments, at least one R^(c) is substitutedmethyl (e.g., —CF₃ or Bn), Et, substituted ethyl (e.g., fluorinatedethyl), Pr, substituted propyl (e.g., fluorinated propyl), Bu, orsubstituted butyl (e.g., fluorinated butyl). In certain embodiments, atleast one R^(c) is a nitrogen protecting group.

In compounds of Formula (I), X is a divalent linker moiety connectingRing B and Ring C. As generally defined herein, X is —C(R^(b))₂—,—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR^(c)—, —C(R^(b))₂C(R^(b))₂—,—C(R^(b))₂C(═O)—, —C(═O)C(R^(b))₂—, (E)-CR^(b)═CR^(b)—,(Z)—CR^(b)═CR^(b)—, —C≡C—, —OC(═O)—, —C(═O)O—, —SC(═O)—, —C(═O)S—,—NR^(c)C(═O)—, —C(═O)NR^(c)—, —OC(R^(b))₂—, —C(R^(b))₂O—, —SC(R^(b))₂—,—C(R^(b))₂S—, —NR^(c)C(R^(b))₂—, —C(R^(b))₂NR^(c)—, —S(═O)O—, —OS(═O)—,—S(═O)NR^(c)—, —NR^(c)S(═O)—, —S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(c)—, or—NR^(c)S(═O)₂—. In certain embodiments, X is —O—. In certainembodiments, X is —S—. In certain embodiments, X is —NR^(c)—, whereinR^(C) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group. In certain embodiments, X is —NH—. In certainembodiments, X is —C(R^(b))₂—. In certain embodiments, X is —CH₂—.

In certain embodiments, L¹ is a bond, —O—, —S—, or —NR^(c)—; and X is—C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR^(c)—, whereinR^(b) and R are as defined herein. In certain embodiments, L¹ is a bondand X is —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR^(c)—,wherein R^(b) and R^(c) are as defined herein. In certain embodiments,L¹ is a bond and X is —O—. In certain embodiments, L¹ is a bond and X is—S—. In certain embodiments, L is a bond and X is —NR^(c)—, whereinR^(aa) is as defined herein. In certain embodiments, L¹ is a bond and Xis —NH—. In certain embodiments, L¹ is —O— and X is —C(R^(b))₂—,—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR^(c)—, wherein R^(b) andR^(c) are as defined herein. In certain embodiments, L¹ is —O— and X is—O—. In certain embodiments, L¹ is —O— and X is —S—. In certainembodiments, L¹ is —O— and X is-NR^(c)—, wherein R^(aa) is as definedherein. In certain embodiments, L¹ is —O— and X is-NH—.

In compounds of Formula (I), L² is a divalent linker moiety connectingRing C and Ring D. L² may be —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—,—S(═O)₂—, —NR^(c)—, —C(R^(b))₂C(R^(b))₂—, —C(R^(b))₂C(═O)—,—C(═O)C(R^(b))₂—, (E)-CR^(b)═CR^(b)—, (Z)—CR^(b)═CR^(b)—, —C≡C—,—OC(═O)—, —C(═O)O—, —SC(═O)—, —C(═O)S—, —NR^(c)C(═O)—, —C(═O)NR^(c)—,—OC(R^(b))₂—, —C(R^(b))₂O—, —SC(R^(b))₂—, —C(R^(b))₂S—,—NR^(c)C(R^(b))₂—, —C(R^(b))₂NR^(c)—, —S(═O)O—, —OS(═O)—, —S(═O)NR^(c)—,—NR^(c)S(═O)—, —S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(c)—, —NR^(c)S(═O)₂—,—OC(═O)O—, —NR^(c)C(═O)O—, —OC(═O)NR^(c)—, —NR^(c)C(═O)NR^(c)—,—C(R^(b))₂C(═O)C(R^(b))₂—, —OC(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)O—,—NR^(c)C(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)NR^(c)—, or a substituted orunsubstituted C₁₋₄ hydrocarbon chain, optionally wherein one or morecarbon units of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR^(c)—, wherein R^(b) andR^(C) are as defined herein. In certain embodiments, L² is—NR^(c)C(═O)—, —C(═O)NR^(c)—, —C(═O)—, —C(R^(b))₂—, —C(R^(b))₂C(═O)—, or—C(R^(b))₂C(═O)NR^(c)—, wherein each instance of R^(b) is independentlyhydrogen, halogen, or substituted or unsubstituted C₁₋₆ alkyl; and eachinstance of R is independently hydrogen, substituted or unsubstitutedC₁₋₆ alkyl, or a nitrogen protecting group. In certain embodiments, L²is —C(═O)—. In certain embodiments, L² is —C(R^(b))₂—. In certainembodiments, L² is —CH₂—. In certain embodiments, L² is —NR^(c)—. Incertain embodiments, L² is —NH—. In certain embodiments, L² is—NR^(c)C(═O)— or —C(═O)NR^(c)—. In certain embodiments, L² is —NHC(═O)—or —C(═O)NH—. In certain embodiments, L² is of the formula: —C(═O)NR—.In certain embodiments, L² is of the formula: —C(═O)NH—. In certainembodiments, L² is of the formula: —NR^(c)C(═O)—. In certainembodiments, L² is of the formula: —NHC(═O)—. In certain embodiments, L²is of the formula: —C(═O)NH— or —NH(═O)—. In certain embodiments, L² isof the formula: —C(R^(b))₂C(═O)—. In certain embodiments, L² is of theformula: —CH₂C(═O)—. In certain embodiments, L² is of the formula:—C(R^(b))₂C(═O)NR^(c)—. In certain embodiments, L² is of the formula:—CH₂C(═O)NR^(c)—. In certain embodiments, L² is of the formula:—CH₂C(═O)NH—.

In certain embodiment, X and L² are para to each other. In certainembodiments, X and L² are meta to each other. In certain embodiments,Ring C is a substituted or unsubstituted phenyl ring, substituted orunsubstituted, monocyclic carbocyclic ring, or substituted orunsubstituted, monocyclic heterocyclic ring. In certain embodiments,Ring C is a substituted or unsubstituted phenyl ring. In certainembodiments, Ring C is a substituted phenyl ring. In certainembodiments, Ring C is an unsubstituted phenyl ring. In certainembodiments, Ring C is a substituted or unsubstituted 1,2-phenylenemoiety. In certain embodiments, Ring C is a substituted or unsubstituted1,3-phenylene moiety. In certain embodiments, Ring C is a substituted orunsubstituted 1,4-phenylene moiety. In certain embodiments, Ring C is asubstituted or unsubstituted substituted or unsubstituted, monocycliccarbocyclic ring. In certain embodiments, wherein Ring C is asubstituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclicring, wherein there are zero, one, or two double bonds in thecarbocyclic ring system, as valency permits. In certain embodiments,Ring C is a substituted or unsubstituted cyclopentylene moiety. Incertain embodiments, Ring C is a substituted or unsubstitutedcyclohexylene moiety. In certain embodiments, Ring C is a substituted orunsubstituted trans-cyclohexylene moiety. In certain embodiments, Ring Cis a substituted or unsubstituted cis-cyclohexylene moiety. In certainembodiments, Ring C is a substituted or unsubstituted 1,2-cyclohexylenemoiety. In certain embodiments, Ring C is a substituted or unsubstituted1,3-cyclohexylene moiety. In certain embodiments, Ring C is asubstituted or unsubstituted 1,4-cyclohexylene moiety. In certainembodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is a substituted or unsubstituted,monocyclic heterocyclic ring. In certain embodiments, Ring C is asubstituted or unsubstituted, 5-membered heterocyclic ring. In certainembodiments, Ring C is a substituted or unsubstituted, 6-memberedheterocyclic ring. In certain embodiments, Ring C is a substituted orunsubstituted, 3- to 7-membered, monocyclic heterocyclic ring, whereinone, two, or three atoms in the heterocyclic ring system areindependently oxygen, nitrogen, or sulfur, as valency permits. Incertain embodiments, Ring C is a substituted or unsubstitutedpiperidinylene moiety. In certain embodiments, Ring C is of the formula:

wherein x indicates the point of attachment to linker X and l indicatesthe point of attachment to linker L². In certain embodiments, Ring C isof the formula:

In certain embodiments, Ring C is of one of the formulae:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of one of the formulae:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of one of the formulae:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of one of the formulae:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of one of the formulae:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of one of the formulae:

In certain embodiments, Ring C is of the formula:

wherein R^(CN) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, ora nitrogen protecting group. In certain embodiments, Ring C is asubstituted or unsubstituted, monocyclic heteroaryl ring. In certainembodiments, Ring C is a substituted or unsubstituted, 5- or 6-membered,monocyclic heteroaryl ring, wherein one, two, three, or four atoms inthe heteroaryl ring system are independently oxygen, nitrogen, orsulfur, as valency permits. In certain embodiments, Ring C issubstituted or unsubstituted pyridinylene. In certain embodiments, RingC is substituted or unsubstituted 2-pyridinylene, wherein X is attachedto the 1-position of the substituted or unsubstituted 2-pyridinylene.

Ring C may be unsubstituted or may be substituted with one or more R^(C)groups. In certain embodiments, at least one R^(C) is halogen. Incertain embodiments, at least one R^(C) is F. In certain embodiments, atleast one R^(C) is Cl. In certain embodiments, at least one R^(C) is Br.In certain embodiments, at least one R^(C) is I (iodine). In certainembodiments, at least one R^(C) is substituted alkyl. In certainembodiments, at least one R^(C) is unsubstituted alkyl. In certainembodiments, at least one R^(C) is C₁₋₆ alkyl. In certain embodiments,at least one R^(C) is methyl. In certain embodiments, at least one R^(C)is ethyl. In certain embodiments, at least one R^(C) is propyl. Incertain embodiments, at least one R^(C) is substituted alkenyl. Incertain embodiments, at least one R^(C) is unsubstituted alkenyl. Incertain embodiments, at least one R^(C) is vinyl. In certainembodiments, at least one R^(C) is substituted alkynyl. In certainembodiments, at least one R^(C) is unsubstituted alkynyl. In certainembodiments, at least one R^(C) is ethynyl. In certain embodiments, atleast one R^(C) is substituted carbocyclyl. In certain embodiments, atleast one R^(C) is unsubstituted carbocyclyl. In certain embodiments, atleast one R^(C) is substituted heterocyclyl. In certain embodiments, atleast one R^(C) is unsubstituted heterocyclyl. In certain embodiments,at least one R^(C) is substituted aryl. In certain embodiments, at leastone R^(C) is unsubstituted aryl. In certain embodiments, at least oneR^(C) is substituted phenyl. In certain embodiments, at least one R^(C)is unsubstituted phenyl. In certain embodiments, at least one R^(C) issubstituted heteroaryl. In certain embodiments, at least one R^(C) isunsubstituted heteroaryl. In certain embodiments, each instance of R^(C)is independently halogen, substituted or unsubstituted C₁₋₆ alkyl, or—OR^(a) (e.g., —OH or —O(substituted or unsubstituted C₁₋₆ alkyl)).

In certain embodiments, Ring C is a substituted phenyl ring and at leastone R^(C) is independently halogen or substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, Ring C is a substituted phenyl ring andat least one R^(C) is independently halogen. In certain embodiments,Ring C is a substituted phenyl ring and at least one R^(C) issubstituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, Ring Cis a substituted phenyl ring and one R^(C) is substituted orunsubstituted C₁₋₆ alkyl. In certain embodiments, Ring C is asubstituted phenyl ring and one R^(C) is unsubstituted C₁₋₆ alkyl (e.g.methyl or ethyl).

Ring C may be unsubstituted or substituted with one or more R^(C) groupsas valency permits. In certain embodiments, Ring C is a substituted orunsubstituted phenyl ring and n is 0, 1, 2, 3, or 4. In certainembodiments, Ring C is a substituted or unsubstituted, monocycliccarbocyclic ring and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, asvalency permits. In certain embodiments, Ring C is a substituted orunsubstituted cyclohexylene moiety and n is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, or 10, as valency permits. In certain embodiments, Ring C is asubstituted or unsubstituted, monocyclic heterocyclic ring and n is 0,1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits. In certainembodiments, Ring C is a substituted or unsubstituted, 6-memberedmonocyclic heterocyclic ring and n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or10, as valency permits.

In certain embodiments, Ring C is unsubstituted, and thus n is 0. Incertain embodiments, n is 1. In certain embodiments, n is 2. In certainembodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5. In certain embodiments, n is 6. In certainembodiments, n is 7. In certain embodiments, n is 8. In certainembodiments, n is 9. In certain embodiments, n is 10.

In compounds of Formula (I), Ring D is a substituted or unsubstitutedphenyl ring, substituted or unsubstituted, monocyclic carbocyclic ring,or substituted or unsubstituted, monocyclic heterocyclic ring. Incertain embodiments, Ring D is a substituted or unsubstituted phenylring. In certain embodiments, Ring D is a substituted phenyl ring. Incertain embodiments, Ring D is an unsubstituted phenyl ring. In certainembodiments, Ring D is a substituted or unsubstituted 1,2-phenylenemoiety. In certain embodiments, Ring D is a substituted or unsubstituted1,3-phenylene moiety. In certain embodiments, Ring D is a substituted orunsubstituted 1,4-phenylene moiety. In certain embodiments, Ring D is asubstituted or unsubstituted substituted or unsubstituted, monocycliccarbocyclic ring. In certain embodiments, Ring D is a substituted orunsubstituted, 3- to 7-membered, monocyclic carbocyclic ring, whereinthere are zero, one, or two double bonds in the carbocyclic ring system,as valency permits. In certain embodiments, Ring D is a substituted orunsubstituted cyclopentylene moiety. In certain embodiments, Ring D is asubstituted or unsubstituted cyclohexylene moiety. In certainembodiments, Ring D is a substituted or unsubstitutedtrans-cyclohexylene moiety. In certain embodiments, Ring D is asubstituted or unsubstituted cis-cyclohexylene moiety. In certainembodiments, Ring D is a substituted or unsubstituted 1,2-cyclohexylenemoiety. In certain embodiments, Ring D is a substituted or unsubstituted1,3-cyclohexylene moiety. In certain embodiments, Ring D is asubstituted or unsubstituted 1,4-cyclohexylene moiety. In certainembodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is a substituted or unsubstituted,monocyclic heterocyclic ring. In certain embodiments, Ring D is asubstituted or unsubstituted, 5-membered heterocyclic ring. In certainembodiments, Ring D is a substituted or unsubstituted, 6-memberedheterocyclic ring. In certain embodiments, Ring D is a substituted orunsubstituted, 3- to 7-membered, monocyclic heterocyclic ring, whereinone, two, or three atoms in the heterocyclic ring system areindependently oxygen, nitrogen, or sulfur, as valency permits. Incertain embodiments, Ring D is a substituted or unsubstitutedpiperidinylene moiety. In certain embodiments, Ring D is of the formula:

wherein l′ indicates the point of attachment to linker L² and eindicates the point of attachment to R^(E). In certain embodiments, RingD is of the formula

In certain embodiments, Ring D is of one of the formulae:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of one of the formulae:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of one of the formulae:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of one of the formulae:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of one of the formulae:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of one of the formulae:

In certain embodiments, Ring D is of the formula:

wherein R^(DN) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, ora nitrogen protecting group.

In certain embodiments, at least one of Ring C and Ring D is asubstituted or unsubstituted phenyl ring. In certain embodiments, Ring Cis a substituted or unsubstituted phenyl ring and Ring D is asubstituted or unsubstituted phenyl ring, substituted or unsubstituted,monocyclic carbocyclic ring, or substituted or unsubstituted, monocyclicheterocyclic ring. In certain embodiments, Ring D is a substituted orunsubstituted phenyl ring and Ring C is a substituted or unsubstitutedphenyl ring, substituted or unsubstituted, monocyclic carbocyclic ring,or substituted or unsubstituted, monocyclic heterocyclic ring. Incertain embodiments, each of Ring C and Ring D is independently asubstituted or unsubstituted phenyl ring. In certain embodiments, Ring Cis a substituted or unsubstituted phenyl ring and Ring D is asubstituted or unsubstituted, monocyclic carbocyclic ring. In certainembodiments, Ring C is a substituted or unsubstituted phenyl ring andRing D is a substituted or unsubstituted cyclohexylene moiety. Incertain embodiments, Ring C is a substituted or unsubstituted phenylring and Ring D is a substituted or unsubstituted heterocyclic ring. Incertain embodiments, Ring C is a substituted or unsubstituted phenylring and Ring D is a substituted or unsubstituted piperidinylene moiety.In certain embodiments, Ring D is a substituted or unsubstituted phenylring and Ring C is a substituted or unsubstituted, monocycliccarbocyclic ring. In certain embodiments, Ring D is a substituted orunsubstituted phenyl ring and Ring C is a substituted or unsubstitutedcyclohexylene moiety. In certain embodiments, Ring D is a substituted orunsubstituted phenyl ring and Ring C is a substituted or unsubstitutedheterocyclic ring. In certain embodiments, Ring D is a substituted orunsubstituted phenyl ring and Ring C is a substituted or unsubstitutedpiperidinylene moiety.

In compounds of Formula (I), Ring D is substituted with R^(E) and mayalso be substituted with one or more R^(D) groups. In certainembodiments, at least one R^(D) is H. In certain embodiments, at leastone R^(D) is halogen. In certain embodiments, at least one R^(D) is F.In certain embodiments, at least one R^(D) is Cl. In certainembodiments, at least one R^(D) is Br. In certain embodiments, at leastone R^(D) is I (iodine). In certain embodiments, at least one R^(D) issubstituted alkyl. In certain embodiments, at least one R^(D) isunsubstituted alkyl. In certain embodiments, at least one R^(D) is C₁₋₆alkyl. In certain embodiments, at least one R^(D) is methyl. In certainembodiments, at least one R^(D) is ethyl. In certain embodiments, atleast one R^(D) is propyl. In certain embodiments, each instance ofR^(D) is independently halogen, substituted or unsubstituted C₁₋₆ alkyl,or —OR^(a) (e.g., —OH or —O(substituted or unsubstituted C₁₋₆ alkyl)).

Ring D may be unsubstituted or substituted with one or more R^(D) groupsas valency permits. In certain embodiments, Ring D is a substituted orunsubstituted phenyl ring and p is 0, 1, 2, 3, or 4. In certainembodiments, Ring D is a substituted or unsubstituted, monocycliccarbocyclic ring and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, as valencypermits. In certain embodiments, Ring D is a substituted orunsubstituted cyclohexylene moiety and p is 0, 1, 2, 3, 4, 5, 6, 7, 8,or 9, as valency permits. In certain embodiments, Ring D is asubstituted or unsubstituted, monocyclic heterocyclic ring and p is 0,1, 2, 3, 4, 5, 6, 7, 8, or 9, as valency permits. In certainembodiments, Ring D is a substituted or unsubstituted, 6-memberedmonocyclic heterocyclic ring and p is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9,as valency permits.

Ring D may be unsubstituted or substituted with one or more R^(D)groups. In certain embodiments, Ring D is unsubstituted, and thus p is0. In certain embodiments, p is 1. In certain embodiments, p is 2. Incertain embodiments, p is 3. In certain embodiments, p is 4.

In certain embodiments, R^(D) is halogen; and p is 1. In certainembodiments, R^(D) is F; and p is 1. In certain embodiments, R^(D) isCl; and p is 1. In certain embodiments, R^(D) is Br; and p is 1. Incertain embodiments, R^(D) is I (iodine); and p is 1. In certainembodiments, R^(D) is substituted alkyl; and p is 1. In certainembodiments, R^(D) is unsubstituted alkyl; and p is 1. In certainembodiments, R^(D) is C₁₋₆ alkyl; and p is 1. In certain embodiments,R^(D) is methyl; and p is 1. In certain embodiments, R^(D) is ethyl,propyl, or butyl; and p is 1. In certain embodiments, each instance ofR^(D) is independently halogen or substituted or unsubstituted alkyl;and p is 2. In certain embodiments, each instance of R^(D) isindependently halogen or C₁₋₆ alkyl; and p is 2.

In compounds of Formula (I), Ring D also includes a substituent R^(E).In certain embodiments, R^(E) comprises a Michael acceptor moiety. ThisMichael acceptor moiety may react with a cysteine residue of a kinase(e.g., PIP4K) to allow covalent attachment of the compound to thekinase. In certain embodiments, the covalent attachment is irreversible.In other embodiments, the covalent attachment is reversible.

As generally defined herein, R^(E) may be any one of Formulae(i-1)-(i-41). In certain embodiments, R^(E) is of Formula (i-1):

In certain embodiments, R^(E) is of Formula (i-2):

In certain embodiments, R^(E) is of Formula (i-3):

In certain embodiments, R^(E) is of Formula (i-4):

In certain embodiments, R^(E) is of Formula (i-5):

In certain embodiments, R^(E) is of Formula (i-6);

In certain embodiments, R^(E) is of Formula (i-7):

In certain embodiments, R^(E) is of Formula (i-8):

In certain embodiments, R^(E) is of Formula (i-9):

In certain embodiments, R^(E) is of Formula (i-10):

In certain embodiments, R^(E) is of Formula (i-11):

In certain embodiments, R^(E) is of Formula (i-12):

In certain embodiments, R^(E) is of Formula (i-13):

In certain embodiments, R^(E) is of Formula (i-14):

In certain embodiments, R^(E) is of Formula (i-15):

In certain embodiments, R^(E) is of Formula (i-16):

In certain embodiments, R^(E) is of Formula (i-17):

In certain embodiments, R^(E) is of Formula (i-18):

In certain embodiments, R^(E) is of Formula (i-19):

In certain embodiments, R^(E) is of Formula (i-20):

In certain embodiments, R^(E) is of Formula (i-21):

In certain embodiments, R^(E) is of Formula (i-22):

In certain embodiments, R^(E) is of Formula (i-23):

In certain embodiments, R^(E) is of Formula (i-24):

In certain embodiments, R^(E) is of Formula (i-25):

In certain embodiments, R^(E) is of Formula (i-26):

In certain embodiments, R^(E) is of Formula (i-27):

In certain embodiments, R^(E) is of Formula (i-28):

In certain embodiments, R^(E) is of Formula (i-29):

In certain embodiments, R^(E) is of Formula (i-30):

In certain embodiments, R^(E) is of Formula (i-31):

In certain embodiments, R^(E) is of Formula (i-32):

In certain embodiments, R^(E) is of Formula (i-33):

In certain embodiments, R^(E) is of Formula (i-34):

In certain embodiments, R^(E) is of Formula (i-35):

In certain embodiments, R^(E) is of Formula (i-36):

In certain embodiments, R^(E) is of Formula (i-37):

In certain embodiments, R^(E) is of Formula (i-38):

In certain embodiments, R^(E) is of Formula (i-39):

In certain embodiments, R^(E) is of Formula (i-40):

In certain embodiments, R^(E) is of Formula (i-41):

In certain embodiments, R^(E) is of Formula (i-1a):

In certain embodiments, R^(E) is of Formula (i-1b):

In certain embodiments, R^(E) is of Formula (i-1c):

In certain embodiments, R^(E) is of Formula (i-1d):

In certain embodiments, R^(E) is of Formula (i-1e):

In certain embodiments, R^(E) is of Formula (i-1f):

In certain embodiments, R^(E) is of Formula (i-1g):

In certain embodiments, R^(E) is

In certain embodiments, R^(E) is of Formula (i-1h)

In certain embodiments, R^(E) is

In certain embodiments, R^(E) is of Formula (i-1a):

In certain embodiments, R^(E) is of Formula (i-1b):

In certain embodiments, R^(E) is of Formula (i-1c):

In certain embodiments, R^(E) is of Formula (i-18a):

In certain embodiments, R^(E) is of Formula (i-18b):

In certain embodiments, R^(E) is of Formula (i-18c):

In certain embodiments, R^(E) is of Formula (i-15a):

In certain embodiments, R^(E) is of Formula (i-15b):

In certain embodiments, R^(E) is of Formula (i-15c):

In certain embodiment, R^(E) and L² are para or meta to each other. Incertain embodiments, R^(E) and L² are meta to each other. In certainembodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, R^(E) and L² are para to each other. In certainembodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of one of the following formulae:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of one of the following formulae:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of one of the following formulae:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In certain embodiments, Ring D is of the formula:

In compounds of Formula (I), L³ is a divalent linker moiety. L³ maycontain 0-4 carbon or hetero atoms in the backbone of L³. L³ may besaturated or unsaturated. L³ may be substituted or unsubstituted. L³ maybe branched or unbranched. In certain embodiments, L³ is a bond. Incertain embodiments, L³ is —O—. In certain embodiments, L³ is —S—. Incertain embodiments, L³ is —NR^(L3a). In certain embodiments, L³ is—NH—. In certain embodiments, L³ is a substituted C₁₋₄ hydrocarbonchain. In certain embodiments, L³ is an unsubstituted C₁₋₄ hydrocarbonchain. In certain embodiments, L³ is —C(R^(L3b))₂—. In certainembodiments, L³ is —CHR^(L3b). In certain embodiments, L³ is —CH₂—. Incertain embodiments, L³ is a substituted C₂ hydrocarbon chain. Incertain embodiments, L³ is an unsubstituted C₂ hydrocarbon chain. Incertain embodiments, L is —C(R^(L3b))₂C(R^(L3b))₂. In certainembodiments, L³ is —CH₂CH₂—. In certain embodiments, L³ istrans-CR^(L3b)═CR^(L3b)—. In certain embodiments, L³ is trans-CH═CH—. Incertain embodiments, L³ is cis-CR^(L3b)═CR^(L3b). In certainembodiments, L³ is cis-CH═CH—. In certain embodiments, L³ is —C═C—. Incertain embodiments, L³ is a substituted C₃ hydrocarbon chain. Incertain embodiments, L³ is an unsubstituted C₃ hydrocarbon chain. Incertain embodiments, L³ is —(CH₂)₃—. In certain embodiments, L³ is—CH═CH—CH₂—, wherein CH═CH is trans or cis. In certain embodiments, L³is —CH₂—CH═CH—, wherein CH═CH is trans or cis. In certain embodiments,L³ is —C═C—CH₂—. In certain embodiments, L³ is —CH₂—C═C—. In certainembodiments, L³ is a substituted C₄ hydrocarbon chain. In certainembodiments, L³ is an unsubstituted C₄ hydrocarbon chain. In certainembodiments, L³ is —(CH₂)₄—. In certain embodiments, L³ is—CH═CH—CH═CH—, wherein each instance of CH═CH is independently trans orcis. In certain embodiments, L³ is —CH═CH—C≡C—, wherein CH═CH is transor cis. In certain embodiments, L³ is —C═C—CH═CH—, wherein CH═CH istrans or cis. In certain embodiments, L³ is —C≡C—C≡C—. In certainembodiments, L³ is a substituted or unsubstituted C₁₋₄ hydrocarbonchain, wherein one or more carbon units of the hydrocarbon chain isreplaced with —O—, —S—, —NR^(L3a)—, —NR^(L3a)C(═O)—, —C(═O)NR^(L3a)—,—SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NR^(L3a)C(═S)—,—C(═S)NR^(L3a)—, trans-CR^(L3b)═CR^(L3b)—, cis-CR^(L3b)═CR^(L3b)—,—C≡C—, —S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(L3a)—, or —NR^(L3a)S(═O)₂—.

In certain embodiments, R^(L3a) is H. In certain embodiments, R^(L3a) issubstituted alkyl. In certain embodiments, R^(L3a) is unsubstitutedalkyl. In certain embodiments, R^(L3a) is C₁₋₆ alkyl. In certainembodiments, R^(L3a) is methyl. In certain embodiments, R^(L3a) isethyl. In certain embodiments, R^(L3a) is propyl. In certainembodiments, R^(L3a) is butyl. In certain embodiments, R^(L3a) is anitrogen protecting group. In certain embodiments, R^(L3a) is Bn, BOC,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

In certain embodiments, at least one R^(L3b) is H. In certainembodiments, at least one R^(L3b) is halogen. In certain embodiments, atleast one R^(L3b) is F. In certain embodiments, at least one R^(L3b) isCl. In certain embodiments, at least one R^(L3b) is Br. In certainembodiments, at least one R^(L3b) is I (iodine). In certain embodiments,at least one R^(L3b) is substituted alkyl. In certain embodiments, atleast one R^(L3b) is unsubstituted alkyl. In certain embodiments, atleast one R^(L3b) is C₁₋₆ alkyl. In certain embodiments, at least oneR^(L3b) is methyl. In certain embodiments, at least one R^(L3b) isethyl. In certain embodiments, at least one R^(L3b) is propyl. Incertain embodiments, at least one R^(L3b) is butyl. In certainembodiments, at least one R^(L3b) is substituted alkenyl. In certainembodiments, at least one R^(L3b) is unsubstituted alkenyl. In certainembodiments, at least one R^(L3b) is vinyl. In certain embodiments, atleast one R^(L3b) is substituted alkynyl. In certain embodiments, atleast one R^(L3b) is unsubstituted alkynyl. In certain embodiments, atleast one R^(L3b) is ethynyl. In certain embodiments, at least oneR^(L3b) is substituted carbocyclyl. In certain embodiments, at least oneR^(L3b) is unsubstituted carbocyclyl. In certain embodiments, at leastone R^(L3b) is substituted heterocyclyl. In certain embodiments, atleast one R^(L3b) is unsubstituted heterocyclyl. In certain embodiments,at least one R^(L3b) is substituted aryl. In certain embodiments, atleast one R^(L3b) is unsubstituted aryl. In certain embodiments, atleast one R^(L3b) is substituted phenyl. In certain embodiments, atleast one R^(L3b) is unsubstituted phenyl. In certain embodiments, atleast one R^(L3b) is substituted heteroaryl. In certain embodiments, atleast one R^(L3b) is unsubstituted heteroaryl. In certain embodiments,at least one R^(L3b) is substituted pyridyl. In certain embodiments, atleast one R^(L3b) is unsubstituted pyridyl. In certain embodiments, twoR^(L3b) groups are joined to form a substituted carbocyclic ring. Incertain embodiments, two R^(L3b) groups are joined to form anunsubstituted carbocyclic ring. In certain embodiments, two R^(L3b)groups are joined to form a substituted heterocyclic ring. In certainembodiments, two R^(L3b) groups are joined to form an unsubstitutedheterocyclic ring.

In compounds of Formula (I), L⁴ is a divalent linker moiety. L⁴ maycontain 0-4 carbon or hetero atoms in the backbone of L⁴. L⁴ may besaturated or unsaturated. L⁴ may be substituted or unsubstituted. L⁴ maybe branched or unbranched. In certain embodiments, L⁴ is a bond. Incertain embodiments, L⁴ is a substituted C₁₋₄ hydrocarbon chain. Incertain embodiments, L⁴ is an unsubstituted C₁₋₄ hydrocarbon chain. Incertain embodiments, L⁴ is —C(R^(L4b))₂—. In certain embodiments, L⁴ is—CHR^(L4b)—. In certain embodiments, L⁴ is —CH₂—. In certainembodiments, L⁴ is a substituted C₂ hydrocarbon chain. In certainembodiments, L⁴ is a unsubstituted C₂ hydrocarbon chain. In certainembodiments, L⁴ is —C(R^(L4b))₂C(R^(L4b))₂—. In certain embodiments, L⁴is —CH₂CH₂—. In certain embodiments, L⁴ is trans-CR^(L4b)═CR^(L4b)—. Incertain embodiments, L⁴ is trans-CH═CH—. In certain embodiments, L⁴ iscis-CR^(L4b)═CR^(L4b)—. In certain embodiments, L⁴ is cis-CH═CH—. Incertain embodiments, L⁴ is —C≡C—. In certain embodiments, L⁴ is asubstituted C₃ hydrocarbon chain. In certain embodiments, L⁴ is anunsubstituted C₃ hydrocarbon chain. In certain embodiments, L⁴ is—(CH₂)₃—. In certain embodiments, L⁴ is —CH═CH—CH₂—, wherein CH═CH istrans or cis. In certain embodiments, L⁴ is —CH₂—CH═CH—, wherein CH═CHis trans or cis. In certain embodiments, L⁴ is —C═C—CH₂—. In certainembodiments, L⁴ is —CH₂—C═C—. In certain embodiments, L⁴ is asubstituted C₄ hydrocarbon chain. In certain embodiments, L⁴ is anunsubstituted C₄ hydrocarbon chain. In certain embodiments, L⁴ is—(CH₂)₄—. In certain embodiments, L⁴ is —CH═CH—CH═CH—, wherein eachinstance of CH═CH is independently trans or cis. In certain embodiments,L⁴ is —CH═CH—C≡C—, wherein CH═CH is trans or cis. In certainembodiments, L⁴ is —C═C—CH═CH—, wherein CH═CH is trans or cis. Incertain embodiments, L⁴ is —C≡C—C≡C—.

In compounds of Formula (I), R^(E) may include a substituent R^(E1). Incertain embodiments, R^(E1) is H. In certain embodiments, R^(E1) ishalogen. In certain embodiments, R^(E1) is F. In certain embodiments,R^(E1) is Cl. In certain embodiments, R^(E1) is Br. In certainembodiments, R^(E1) is I (iodine). In certain embodiments, R^(E1) issubstituted acyl. In certain embodiments, R^(E1) is unsubstituted acyl.In certain embodiments, R^(E1) is acetyl. In certain embodiments, R^(E1)is substituted acetyl. In certain embodiments, R^(E1) is substitutedalkyl. In certain embodiments, R^(E1) is unsubstituted alkyl. In certainembodiments, R^(E1) is C₁₋₆ alkyl. In certain embodiments, R^(E1) ismethyl. In certain embodiments, R^(E1) is ethyl. In certain embodiments,R^(E1) is propyl. In certain embodiments, R^(E1) is butyl. In certainembodiments, R^(E1) is substituted alkenyl. In certain embodiments,R^(E1) is unsubstituted alkenyl. In certain embodiments, R^(E1) isvinyl. In certain embodiments, R^(E1) is substituted alkynyl. In certainembodiments, R^(E1) is unsubstituted alkynyl. In certain embodiments,R^(E1) is ethynyl. In certain embodiments, R^(E1) is substitutedcarbocyclyl. In certain embodiments, R^(E1) is unsubstitutedcarbocyclyl. In certain embodiments, R^(E1) is substituted heterocyclyl.In certain embodiments, R^(E1) is unsubstituted heterocyclyl. In certainembodiments, R^(E1) is substituted aryl. In certain embodiments, R^(E1)is unsubstituted aryl. In certain embodiments, R^(E1) is substitutedphenyl. In certain embodiments, R^(E1) is unsubstituted phenyl. Incertain embodiments, R^(E1) is substituted heteroaryl. In certainembodiments, R^(E1) is unsubstituted heteroaryl. In certain embodiments,R^(E1) is substituted pyridyl. In certain embodiments, R^(E1) isunsubstituted pyridyl. In certain embodiments, R^(E1) is —CN. In certainembodiments, R^(E1) is —OR^(E1a). In certain embodiments, R^(E1) is—N(R^(E1a))₂. In certain embodiments, R^(E1) is —SR^(E1a). In certainembodiments, R^(E1) is-CH₂OR^(E1a). In certain embodiments, R^(E1) is—CH₂N(R^(E1a))₂. In certain embodiments, R^(E1) is-CH₂SR^(E1a).

In certain embodiments, when R^(E1) is —OR^(E1a), —N(R^(E1a))₂,—SR^(E1a), —CH₂OR^(E1a)CH₂N(R^(E1a))₂, or —CH₂SR^(E1a), R^(E1a) is H. Incertain embodiments, R^(E1) is —Si(R^(E1a))₃, optionally wherein eachinstance of R^(E1a) is independently unsubstituted C₁₋₆ alkyl orunsubstituted phenyl. In certain embodiments, R^(E1) is —Si(Me)₃). Incertain embodiments, R^(E1a) is substituted acyl. In certainembodiments, R^(E1a) is unsubstituted acyl. In certain embodiments,R^(E1a) is acetyl. In certain embodiments, R^(E1a) is substitutedacetyl. In certain embodiments, R^(E1a) is substituted alkyl. In certainembodiments, R^(E1)a is unsubstituted alkyl. In certain embodiments,R^(E1a) is C₁₋₆ alkyl. In certain embodiments, R^(E1a) is methyl. Incertain embodiments, R^(E1a) is ethyl. In certain embodiments, R^(E1a)is propyl. In certain embodiments, R^(E1a) is butyl. In certainembodiments, R^(E1a) is substituted alkenyl. In certain embodiments,R^(E1a) is unsubstituted alkenyl. In certain embodiments, R^(E1a) isvinyl. In certain embodiments, R^(E1a) is substituted alkynyl. Incertain embodiments, R^(E1a) is unsubstituted alkynyl. In certainembodiments, R^(E1a) is ethynyl. In certain embodiments, R^(E1a) issubstituted carbocyclyl. In certain embodiments, R^(E1a) isunsubstituted carbocyclyl. In certain embodiments, R^(E1a) issubstituted heterocyclyl. In certain embodiments, R^(E1a) isunsubstituted heterocyclyl. In certain embodiments, R^(E1a) issubstituted aryl. In certain embodiments, R^(E1a) is unsubstituted aryl.In certain embodiments, R^(E1a) is substituted phenyl. In certainembodiments, R^(E1a) is unsubstituted phenyl. In certain embodiments,R^(E1a) is substituted heteroaryl. In certain embodiments, R^(E1a) isunsubstituted heteroaryl. In certain embodiments, R^(E1a) is substitutedpyridyl. In certain embodiments, R^(E1a) is unsubstituted pyridyl. Incertain embodiments, R^(E1a) is a nitrogen protecting group whenattached to a nitrogen atom. In certain embodiments, R^(E1a) is Bn, BOC,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attachedto a nitrogen atom. In certain embodiments, R^(E1a) is an oxygenprotecting group when attached to an oxygen atom. In certainembodiments, R^(E1a) is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP,t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygenatom. In certain embodiments, R^(E1a) is a sulfur protecting group whenattached to a sulfur atom. In certain embodiments, R^(E1a) isacetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl,or triphenylmethyl when attached to a sulfur atom. In certainembodiments, two R^(E1a) groups are joined to form a substitutedheterocyclic ring. In certain embodiments, two R^(E1a) groups are joinedto form an unsubstituted heterocyclic ring.

In compounds of Formula (I), R^(E) may include a substituent R^(E2). Incertain embodiments, R^(E2) is H. In certain embodiments, R^(E2) ishalogen. In certain embodiments, R^(E2) is F. In certain embodiments,R^(E2) is Cl. In certain embodiments, R^(E2) is Br. In certainembodiments, R^(E2) is I (iodine). In certain embodiments, R^(E2) issubstituted acyl. In certain embodiments, R^(E2) is unsubstituted acyl.In certain embodiments, R^(E2) is acetyl. In certain embodiments, R^(E2)is substituted acetyl. In certain embodiments, R^(E2) is substitutedalkyl. In certain embodiments, R^(E2) is unsubstituted alkyl. In certainembodiments, R^(E2) is C₁₋₆ alkyl. In certain embodiments, R^(E2) ismethyl. In certain embodiments, R^(E2) is ethyl. In certain embodiments,R^(E2) is propyl. In certain embodiments, R^(E2) is butyl. In certainembodiments, R^(E2) is substituted alkenyl. In certain embodiments,R^(E2) is unsubstituted alkenyl. In certain embodiments, R^(E2) isvinyl. In certain embodiments, R^(E2) is substituted alkynyl. In certainembodiments, R^(E2) is unsubstituted alkynyl. In certain embodiments,R^(E2) is ethynyl. In certain embodiments, R^(E2) is substitutedcarbocyclyl. In certain embodiments, R^(E2) is unsubstitutedcarbocyclyl. In certain embodiments, R^(E2) is substituted heterocyclyl.In certain embodiments, R^(E2) is unsubstituted heterocyclyl. In certainembodiments, R^(E2) is substituted aryl. In certain embodiments, R^(E2)is unsubstituted aryl. In certain embodiments, R^(E2) is substitutedphenyl. In certain embodiments, R^(E2) is unsubstituted phenyl. Incertain embodiments, R^(E2) is substituted heteroaryl. In certainembodiments, R^(E2) is unsubstituted heteroaryl. In certain embodiments,R^(E2) is substituted pyridyl. In certain embodiments, R^(E2) isunsubstituted pyridyl. In certain embodiments, R^(E2) is —CN. In certainembodiments, R^(E2) is —OR^(E2a). In certain embodiments, R^(E2) is—N(R^(E2a))₂. In certain embodiments, R^(E2) is —SR^(E2a). In certainembodiments, R^(E2) is-CH₂OR^(E2a). In certain embodiments, R^(E2) is—CH₂N(R^(E2a))₂. In certain embodiments, R^(E2) is-CH₂SR^(E2a).

In certain embodiments, when R^(E2) is —OR^(E2a), —N(R^(E2a))₂,—SR^(E2a), —CH₂OR^(E2a), —CH₂N(R^(E2a))₂, or —CH₂SR^(E2a), R^(E2a) is H.In certain embodiments, R^(E2a) is substituted acyl. In certainembodiments, R^(E2a) is unsubstituted acyl. In certain embodiments,R^(E2a) is acetyl. In certain embodiments, R^(E2a) is substitutedacetyl. In certain embodiments, R^(E2a) is substituted alkyl. In certainembodiments, R^(E2a) is unsubstituted alkyl. In certain embodiments,R^(E2a) is C₁₋₆ alkyl. In certain embodiments, R^(E2a) is methyl. Incertain embodiments, R^(E2a) is ethyl. In certain embodiments, R^(E2a)is propyl. In certain embodiments, R^(E2a) is butyl. In certainembodiments, R^(E2a) is substituted alkenyl. In certain embodiments,R^(E2a) is unsubstituted alkenyl. In certain embodiments, R^(E2a) isvinyl. In certain embodiments, R^(E2a) is substituted alkynyl. Incertain embodiments, R^(E2a) is unsubstituted alkynyl. In certainembodiments, R^(E2a) is ethynyl. In certain embodiments, R^(E2a) issubstituted carbocyclyl. In certain embodiments, R^(E2a) isunsubstituted carbocyclyl. In certain embodiments, R^(E2a) issubstituted heterocyclyl. In certain embodiments, R^(E2a) isunsubstituted heterocyclyl. In certain embodiments, R^(E2a) issubstituted aryl. In certain embodiments, R^(E2a) is unsubstituted aryl.In certain embodiments, R^(E2a) is substituted phenyl. In certainembodiments, R^(E2a) is unsubstituted phenyl. In certain embodiments,R^(E2a) is substituted heteroaryl. In certain embodiments, R^(E2a) isunsubstituted heteroaryl. In certain embodiments, R^(E2a) is substitutedpyridyl. In certain embodiments, R^(E2a) is unsubstituted pyridyl. Incertain embodiments, R^(E2a) is a nitrogen protecting group whenattached to a nitrogen atom. In certain embodiments, R^(E2a) is Bn, BOC,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attachedto a nitrogen atom. In certain embodiments, R^(E2a) is an oxygenprotecting group when attached to an oxygen atom. In certainembodiments, R^(E2a) is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP,t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygenatom. In certain embodiments, R^(E2a) is a sulfur protecting group whenattached to a sulfur atom. In certain embodiments, R^(E2a) isacetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl,or triphenylmethyl when attached to a sulfur atom. In certainembodiments, two R^(E2a) groups are joined to form a substitutedheterocyclic ring. In certain embodiments, two R^(E2a) groups are joinedto form an unsubstituted heterocyclic ring.

In compounds of Formula (I), R^(E) may include a substituent R^(E3). Incertain embodiments, R^(E3) is H. In certain embodiments, R^(E3) ishalogen. In certain embodiments, R^(E3) is F. In certain embodiments,R^(E3) is Cl. In certain embodiments, R^(E3) is Br. In certainembodiments, R^(E3) is I (iodine). In certain embodiments, R^(E3) issubstituted acyl. In certain embodiments, R^(E3) is unsubstituted acyl.In certain embodiments, R^(E3) is acetyl. In certain embodiments, R^(E3)is substituted acetyl. In certain embodiments, R^(E3) is substitutedalkyl. In certain embodiments, R^(E3) is unsubstituted alkyl. In certainembodiments, R^(E3) is C₁₋₆ alkyl. In certain embodiments, R^(E3) ismethyl. In certain embodiments, R^(E3) is ethyl. In certain embodiments,R^(E3) is propyl. In certain embodiments, R^(E3) is butyl. In certainembodiments, R^(E3) is substituted alkenyl. In certain embodiments,R^(E3) is unsubstituted alkenyl. In certain embodiments, R^(E3) isvinyl. In certain embodiments, R^(E3) is substituted alkynyl. In certainembodiments, R^(E3) is unsubstituted alkynyl. In certain embodiments,R^(E3) is ethynyl. In certain embodiments, R^(E3) is substitutedcarbocyclyl. In certain embodiments, R^(E3) is unsubstitutedcarbocyclyl. In certain embodiments, R^(E3) is substituted heterocyclyl.In certain embodiments, R^(E3) is unsubstituted heterocyclyl. In certainembodiments, R^(E3) is substituted aryl. In certain embodiments, R^(E3)is unsubstituted aryl. In certain embodiments, R^(E3) is substitutedphenyl. In certain embodiments, R^(E3) is unsubstituted phenyl. Incertain embodiments, R^(E3) is substituted heteroaryl. In certainembodiments, R^(E3) is unsubstituted heteroaryl. In certain embodiments,R^(E3) is substituted pyridyl. In certain embodiments, R^(E3) isunsubstituted pyridyl. In certain embodiments, R^(E3) is —CN. In certainembodiments, R^(E3) is —OR^(E3a). In certain embodiments, R^(E3) is—N(R^(E3a))₂. In certain embodiments, R^(E3) is —SR^(E3a). In certainembodiments, R^(E3) is-CH₂OR^(E3a). In certain embodiments, R^(E3) is—CH₂N(R^(E3a))₂. In certain embodiments, R^(E3) is —CH₂SR^(E3a).

In certain embodiments, when R^(E3) is —OR^(E3a), —N(R^(E3a))₂,—SR^(E3a), —CH₂OR^(E3a)CH₂N(R^(E3a))₂, or —CH₂SR^(E3a), R^(E3a) is H. Incertain embodiments, R^(E3a) is substituted acyl. In certainembodiments, R^(E3a) is unsubstituted acyl. In certain embodiments,R^(E3a) is acetyl. In certain embodiments, R^(E3a) is substitutedacetyl. In certain embodiments, R^(E3a) is substituted alkyl. In certainembodiments, R^(E3a) is unsubstituted alkyl. In certain embodiments,R^(E3a) is C₁₋₆ alkyl. In certain embodiments, R^(E3a) is methyl. Incertain embodiments, R^(E3a) is ethyl. In certain embodiments, R^(E3a)is propyl. In certain embodiments, R^(E3a) is butyl. In certainembodiments, R^(E3a) is substituted alkenyl. In certain embodiments,R^(E3a) is unsubstituted alkenyl. In certain embodiments, R^(E3a) isvinyl. In certain embodiments, R^(E3a) is substituted alkynyl. Incertain embodiments, R^(E3a) is unsubstituted alkynyl. In certainembodiments, R^(E3a) is ethynyl. In certain embodiments, R^(E3a) issubstituted carbocyclyl. In certain embodiments, R^(E3a) isunsubstituted carbocyclyl. In certain embodiments, R^(E3a) issubstituted heterocyclyl. In certain embodiments, R^(E3a) isunsubstituted heterocyclyl. In certain embodiments, R^(E3a) issubstituted aryl. In certain embodiments, R^(E3a) is unsubstituted aryl.In certain embodiments, R^(E3a) is substituted phenyl. In certainembodiments, R^(E3a) is unsubstituted phenyl. In certain embodiments,R^(E3a) is substituted heteroaryl. In certain embodiments, R^(E3a) isunsubstituted heteroaryl. In certain embodiments, R^(E3a) is substitutedpyridyl. In certain embodiments, R^(E3a) is unsubstituted pyridyl. Incertain embodiments, R^(E3a) is a nitrogen protecting group whenattached to a nitrogen atom. In certain embodiments, R^(E3a) is Bn, BOC,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attachedto a nitrogen atom. In certain embodiments, R^(E3a) is an oxygenprotecting group when attached to an oxygen atom. In certainembodiments, R^(E3a) is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP,t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygenatom. In certain embodiments, R^(E3a) is a sulfur protecting group whenattached to a sulfur atom. In certain embodiments, R^(E3a) isacetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl,or triphenylmethyl when attached to a sulfur atom. In certainembodiments, two R^(E3a) groups are joined to form a substitutedheterocyclic ring. In certain embodiments, two R^(E3a) groups are joinedto form an unsubstituted heterocyclic ring.

In compounds of Formula (I), R^(E1) and R^(E3), or R^(E2) and R^(E3), orR^(E1) and R^(E2) may be joined to form a substituted or unsubstitutedcarbocyclic or substituted or unsubstituted heterocyclic ring. Incertain embodiments, R^(E1) and R^(E3) are joined to form a substitutedor unsubstituted carbocyclic ring. In certain embodiments, R^(E1) andR^(E3) are joined to form a substituted or unsubstituted heterocyclicring. In certain embodiments, R^(E2) and R^(E3) are joined to form asubstituted or unsubstituted carbocyclic ring. In certain embodiments,R^(E2) and R^(E3) are joined to form a substituted or unsubstitutedheterocyclic ring. In certain embodiments, R^(E) and R^(E2) are joinedto form a substituted or unsubstituted carbocyclic ring. In certainembodiments, R^(E1) and R^(E2) are joined to form a substituted orunsubstituted heterocyclic ring.

In compounds of Formula (I), R^(E) may include a substituent R^(E). Incertain embodiments, R^(E4) is a leaving group. In certain embodiments,R^(E4) is halogen. In certain embodiments, R^(E4) is F. In certainembodiments, R^(E4) is Cl. In certain embodiments, R^(E4) is Br. Incertain embodiments, R^(E4) is I (iodine). In certain embodiments, R is—OS(═O)_(w)R^(E4a). In certain embodiments, w is 1. In certainembodiments, w is 2. In certain embodiments, R^(E) is—OMs. In certainembodiments, R^(E4) is—OTf. In certain embodiments, R^(E4) is—OTs. Incertain embodiments, R^(E4) is —OBs. In certain embodiments, R^(E) is2-nitrobenzenesulfonyloxy. In certain embodiments, R^(E4) is —OR^(aa).In certain embodiments, R^(E) is —OMe. In certain embodiments, R^(E4) is—OCF₃. In certain embodiments, R^(E4) is —OPh. In certain embodiments,R^(E4) is —OC(═O)RH^(E4a). In certain embodiments, R^(E4) is —OC(═O)Me.In certain embodiments, R^(E4) is —OC(═O)CF₃. In certain embodiments,R^(E4) is —OC(═O)Ph. In certain embodiments, R^(E4) is —OC(═O)Cl. Incertain embodiments, R is —OC(═O)OR^(a). In certain embodiments, R^(E4)is —OC(═O)OMe. In certain embodiments, R^(E4) is —OC(═O)O(t-Bu).

In certain embodiments, R^(E4a) is substituted alkyl. In certainembodiments, R^(E4a) is unsubstituted alkyl. In certain embodiments,R^(E4a) is C₁₋₆ alkyl. In certain embodiments, R^(E)a is methyl. Incertain embodiments, R^(E)a is ethyl. In certain embodiments, R^(E4a) ispropyl. In certain embodiments, R^(E4a) is butyl. In certainembodiments, R^(E4a) is substituted alkenyl. In certain embodiments,R^(E4a) is unsubstituted alkenyl. In certain embodiments, R^(E4a) isvinyl. In certain embodiments, R^(E4a) is substituted alkynyl. Incertain embodiments, R^(E4a) is unsubstituted alkynyl. In certainembodiments, R^(E4a) is ethynyl. In certain embodiments, R^(E)a issubstituted carbocyclyl. In certain embodiments, R^(E4a) isunsubstituted carbocyclyl. In certain embodiments, R^(E4a) issubstituted heterocyclyl. In certain embodiments, R^(E4a) isunsubstituted heterocyclyl. In certain embodiments, R^(E4a) issubstituted aryl. In certain embodiments, R^(E4a) is unsubstituted aryl.In certain embodiments, R^(E4a) is substituted phenyl. In certainembodiments, R^(E4a) is unsubstituted phenyl. In certain embodiments,R^(E4a) is substituted heteroaryl. In certain embodiments, R^(E4a) isunsubstituted heteroaryl. In certain embodiments, R^(E4a) is substitutedpyridyl. In certain embodiments, R^(E4a) is unsubstituted pyridyl.

In compounds of Formula (I), R^(E) may include a Y group. In certainembodiments, Y is ═O. In certain embodiments, Y is —O—. In certainembodiments, Y is ═S. In certain embodiments, Y is —S—. In certainembodiments, Y is ═NR^(E6). In certain embodiments, Y is —NR^(E6)—. Incertain embodiments, Y is ═NH. In certain embodiments, Y is —NH—. Incertain embodiments, R^(E6) is H. In certain embodiments, R^(E6) issubstituted or unsubstituted C₁₋₆ alkyl (e.g., —CH₃). In certainembodiments, R^(E6) is a nitrogen protecting group (e.g., Bn, BOC, Cbz,Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

In compounds of Formula (I), R^(E) may include a substituent R^(E5),which is halogen. In certain embodiments, R^(E5) is F, Cl, Br, or I(iodine).

In certain embodiments, a is 1. In certain embodiments, a is 2.

In certain embodiments, z is 0. In certain embodiments, z is 1. Incertain embodiments, z is 2. In certain embodiments, z is 3. In certainembodiments, z is 4. In certain embodiments, z is 5. In certainembodiments, z is 6.

In certain embodiments, R^(E) is of Formula (i-1); and R^(E1) ishydrogen. In certain embodiments, R^(E) is of Formula (i-1); and R^(E2)is hydrogen. In certain embodiments, R^(E) is of Formula (i-1); andR^(E3) is hydrogen. In certain embodiments, R^(E) is of Formula (i-1);and R^(E2) and R^(E3) are each hydrogen. In certain embodiments, R^(E)is of Formula (i-1); and R^(E1), R^(E2) and R^(E3) are each hydrogen. Incertain embodiments, R^(E) is of Formula (i-1); and R^(E1) is—CH₂N(R^(E1a)). In certain embodiments, R^(E) is of Formula (i-1);R^(E1) is —CH₂N(R^(E1a)); and R^(E1a) is C₁₋₆ alkyl. In certainembodiments, R^(E) is of Formula (i-1); R^(E1) is —CH₂N(R^(E1a)); andR^(E1a) is methyl. In certain embodiments, R^(E) is of Formula (i-1);and R^(E2) is —CH₂N(R^(E2a)). In certain embodiments, R^(E) is ofFormula (i-1); R^(E2) is —CH₂N(R^(E2a)); and R^(E2a) is C₁₋₆ alkyl. Incertain embodiments, R^(E) is of Formula (i-1); R^(E2) is—CH₂N(R^(E2a)); and R^(E2a) is methyl. In certain embodiments, R^(E) isof Formula (i-1); and R^(E3) is —CH₂N(R^(E3a)). In certain embodiments,R^(E) is of Formula (i-1); R^(E3) is —CH₂N(R^(E3a)); and R^(E3a) is C₁₋₆alkyl. In certain embodiments, R^(E) is of Formula (i-1); R^(E3) is—CH₂N(R^(E3a)); and R^(E3a) is methyl. In certain embodiments, R^(E) isof Formula (i-1); and Y is ═O. In certain embodiments, R^(E) is ofFormula (i-1); and L³ is —NR^(L3a). In certain embodiments, R^(E) is ofFormula (i-1); and L³ is —NH—. In certain embodiments, R^(E) is of theformula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of Formula (i-3); and R^(E1) ishydrogen. In certain embodiments, R^(E) is of Formula (i-3); and R^(E1)is —CH₂N(R^(E1a)). In certain embodiments, R^(E) is of Formula (i-3);and R^(E1) is —Si(R^(E1a))₃ (e.g., —Si(Me)₃). In certain embodiments,R^(E) is of Formula (i-3); R^(E1) is —CH₂N(R^(E1a)); and R^(E1a) is C₁₋₆alkyl. In certain embodiments, R^(E) is of Formula (i-3); R^(E1) is—CH₂N(R^(E1a)); and R^(E1a) is methyl. In certain embodiments, R^(E) isof Formula (i-3); and Y is ═O. In certain embodiments, R^(E) is ofFormula (i-3); and L³ is —NR^(L3a)—. In certain embodiments, R^(E) is ofFormula (i-3); and L³ is —NH—.

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is not of the formula:

In certain embodiments, the compound of Formula (I) is of Formula (II):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula(II-a):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula(II-b):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula (III):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula(III-a):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula(III-b):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula (IV):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula(IV-a):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula (V):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula (V-a):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula (V-b):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula (VI):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of Formula(VI-a):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I) is of one of thefollowing formulae:

or a pharmaceutically acceptable salt thereof.

In certain embodiments of Formulae (I)-(VI), R^(E) is of Formula (i-1);and L³ is —NR^(L3a)—. In certain embodiments of Formulae (I)-(VI), R^(E)is of Formula (i-1); and L³ is —NH—. In certain embodiments of Formulae(I)-(VI), R^(E) is of the formula:

In certain embodiments of Formulae (I)-(VI), R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof. In certain embodiments,the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof. In certain embodiments,the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof. In certain embodiments,the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof. In certain embodiments,the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof. In certain embodiments,the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof. In certain embodiments,the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof. In certain embodiments,the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof. In certain embodiments,the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (I) is substantially pure.In certain embodiments, a compound of Formula (I) is a substantiallypure stereoisomer. In certain embodiments, the compounds of the presentinvention are compounds of Formula (I), and pharmaceutically acceptablesalts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, isotopically labeled derivatives, and prodrugs thereof.In certain embodiments, the compounds of the present invention arecompounds of Formula (I), and pharmaceutically acceptable salts andstereoisomers thereof. In certain embodiments, the compounds of thepresent invention are compounds of Formula (I), and pharmaceuticallyacceptable salts thereof. In certain embodiments, the compounds of thepresent invention are a stereoisomeric mixture of compounds of Formula(I), and pharmaceutically acceptable salts thereof. In certainembodiments, the compounds of the present invention are a racemicstereoisomeric mixture of compounds of Formula (I), and pharmaceuticallyacceptable salts thereof.

The compounds of the present invention may bear multiple binding motifsfor binding to a kinase. The compounds of the present invention may alsoinhibit a kinase. In certain embodiments, the kinase is a proteinkinase. In certain embodiments, the protein kinase is a CDK (e.g., CDK7,CDK12, and/or CDK13). In certain embodiments, the kinase is a lipidkinase. In certain embodiments, the protein kinase is a PIP4K. Incertain embodiments, the PIP4K is a PIP4K2. In certain embodiments, thePIP4K2 is PIP4K2A protein. In certain embodiments, the PIP4K2 is PIP4K2Bprotein. In certain embodiments, the PIP4K2 is PIPK2C protein. Ring A ofthe inventive compounds may be accommodated by a hydrophobic pocket inthe ATP-binding site of the kinase (e.g., a lipid kinase such as PIP4K2enzyme). Functionalities on Rings A and B may bind to residues of thekinase (e.g., a lipid kinase such as PIP4K2 enzyme). For example, Ring Amay form a hydrogen bond with a Cys residue of PIP4K (e.g. Cys293 ofPIP4K2A enzyme or Cys307 and/or Cys318 of PIP4K2B enzyme). Functionalgroups of R^(E) may form one or more hydrogen bonds with the kinase(e.g., a lipid kinase such as PIP4K2 enzyme). Moreover, the Michaelacceptor moiety of R^(E) may react with a cysteine residue of the kinase(e.g., a lipid kinase such as PIP4K2 enzyme) to allow covalentattachment of the compound to the kinase (e.g., a lipid kinase such as aPIP4K2 enzyme).

In certain embodiments, the provided compound is capable of covalentlymodifying Cys293 of PI5P4Kα. In certain embodiments, the providedcompound is capable of covalently modifying Cys307 and/or Cys318 ofPI5P4Kβ. In certain embodiments, the provided compound is capable ofcovalently modifying Cys313 of PI5P4Kγ while Cys313 is based on thesequence alignment.

The compounds of the present invention are thought to be kinaseinhibitors. In certain embodiments, the inventive compounds areinhibitors of protein kinases. In certain embodiments, the inventivecompounds are CDK inhibitors. In certain embodiments, the inventivecompounds are CDK7 inhibitors. In certain embodiments, the inventivecompounds are CDK12 inhibitors. In certain embodiments, the inventivecompounds are CDK13 inhibitors. In certain embodiments, the inventivecompounds are inhibitors of lipid kinases. In certain embodiments, theinventive compounds are PIPK inhibitors. In certain embodiments, theinventive compounds are PIP4K2 inhibitors. In certain embodiments, theinventive compounds are PIP4K2A inhibitors. In certain embodiments, theinventive compounds are PIP4K2B inhibitors. In certain embodiments, theinventive compounds are PIP4K2C inhibitors. In certain embodiments, theinventive compounds are selective CDK inhibitors (e.g., being moreactive in inhibiting a CDK than a non-CDK kinase). In certainembodiments, the inventive compounds are selective CDK7 inhibitors(e.g., being more active in inhibiting CDK7 than a non-CDK7 kinase). Incertain embodiments, the inventive compounds are selective CDK12inhibitors. In certain embodiments, the inventive compounds areselective CDK13 inhibitors. In certain embodiments, the inventivecompounds are selective PIPK inhibitors (e.g., being more active ininhibiting a PIPK than a non-PIPK kinase). In certain embodiments, theinventive compounds are selective PIP4K2 inhibitors (e.g., being moreactive in inhibiting PIP4K2 than a non-PIP4K2 kinase). In certainembodiments, the inventive compounds are selective PIP4K2A inhibitors.In certain embodiments, the inventive compounds are selective PIP4K2Binhibitors. In certain embodiments, the inventive compounds areselective PIP4K2C inhibitors.

The selectivity of an inventive compound for a first kinase (e.g., lipidkinase) over a second kinase (e.g., a non-lipid kinase) may be measuredby the quotient of the IC₅₀ (half maximal inhibitory concentration)value of the inventive compound in inhibiting the activity of the secondkinase over the IC₅₀ value of the inventive compound in inhibiting theactivity of the first kinase. The selectivity of an inventive compoundfor a first kinase over a second kinase may also be measured by thequotient of the K_(d) (dissociation constant) value of an adduct(covalent or non-covalent) of the inventive compound and the secondkinase over the K_(d) value of an adduct of the inventive compound andthe first kinase. In certain embodiments, the selectivity is at leastabout 1-fold, at least about 2-fold, at least about 5-fold, at leastabout 10-fold, at least about 30-fold, at least about 100-fold, at leastabout 300-fold, at least about 1,000-fold, at least about 3,000-fold, atleast about 10,000-fold, at least about 30,000-fold, or at least about100,000-fold. In certain embodiments, IC₅₀ values are measured by afunctional antagonist assay. In certain embodiments, IC₅₀ values aremeasured by a competition binding assay. In certain embodiments, IC₅₀values are measured by a method described herein. In certainembodiments, K_(d) values are measured by a nuclear magnetic resonancemethod (e.g., a linearization method and a curve fitting method). Incertain embodiments, K_(d) values are measured by a mass spectrometrymethod (e.g., a one-ligand one-binding-site ESI-MS method).

The compounds as described herein differ in the Ring B moiety from thecompounds disclosed in WO2014/063068 published Apr. 24, 2014. Thecompounds as described herein are also differ in the Ring A moiety fromthe compounds disclosed in International Application No.PCT/US2015/027312 filed Apr. 23, 2015.

Pharmaceutical Compositions, Kits, and Administration

The present invention provides pharmaceutical compositions comprising acompound of Formula (I), e.g., a compound of Formula (I), or apharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, as described herein, and optionally a pharmaceuticallyacceptable excipient. In certain embodiments, the pharmaceuticalcomposition of the invention comprises a compound of Formula (I), or apharmaceutically acceptable salt thereof, and optionally apharmaceutically acceptable excipient. In certain embodiments, thecompound of Formula (I), or a pharmaceutically acceptable salt, solvate,hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopicallylabeled derivative, or prodrug thereof, is provided in an effectiveamount in the pharmaceutical composition. In certain embodiments, theeffective amount is a therapeutically effective amount. In certainembodiments, the effective amount is a prophylactically effectiveamount.

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound of Formula (I) (the“active ingredient”) into association with a carrier and/or one or moreother accessory ingredients, and then, if necessary and/or desirable,shaping and/or packaging the product into a desired single- ormulti-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage such as, for example, one-half or one-third ofsuch a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose, and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g. acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g.bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)),long chain amino acid derivatives, high molecular weight alcohols (e.g.stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate,ethylene glycol distearate, glyceryl monostearate, and propylene glycolmonostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene,polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer),carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium,powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acidesters (e.g. polyoxyethylene sorbitan monolaurate (Tween 20),polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate(Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate(Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitanmonooleate (Span 80)), polyoxyethylene esters (e.g. polyoxyethylenemonostearate (Myrj 45), polyoxyethylene hydrogenated castor oil,polyethoxylated castor oil, polyoxymethylene stearate, and Solutol),sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g.Cremophor™), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether(Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate,triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate,oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68,Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride,benzalkonium chloride, docusate sodium, and/or mixtures thereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives. In certainembodiments, the preservative is an antioxidant. In other embodiments,the preservative is a chelating agent.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixturesthereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor™,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions which can be used include polymericsubstances and waxes. Solid compositions of a similar type can beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugar as well as high molecular weightpolyethylene glycols and the like.

The active ingredient can be in a micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets, and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compoundof this invention may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier and/or any needed preservativesand/or buffers as can be required. Additionally, the present inventioncontemplates the use of transdermal patches, which often have the addedadvantage of providing controlled delivery of an active ingredient tothe body. Such dosage forms can be prepared, for example, by dissolvingand/or dispensing the active ingredient in the proper medium.Alternatively or additionally, the rate can be controlled by eitherproviding a rate controlling membrane and/or by dispersing the activeingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices. Intradermalcompositions can be administered by devices which limit the effectivepenetration length of a needle into the skin. Jet injection deviceswhich deliver liquid vaccines to the dermis via a liquid jet injectorand/or via a needle which pierces the stratum corneum and produces a jetwhich reaches the dermis are suitable. Ballistic powder/particledelivery devices which use compressed gas to accelerate the compound inpowder form through the outer layers of the skin to the dermis aresuitable. Alternatively or additionally, conventional syringes can beused in the classical mantoux method of intradermal administration.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi liquid preparations such as liniments,lotions, oil-in-water and/or water-in-oil emulsions such as creams,ointments, and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations may, for example, comprise fromabout 1% to about 10% (w/w) active ingredient, although theconcentration of the active ingredient can be as high as the solubilitylimit of the active ingredient in the solvent. Formulations for topicaladministration may further comprise one or more of the additionalingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self-propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition of theinvention. Another formulation suitable for intranasal administration isa coarse powder comprising the active ingredient and having an averageparticle from about 0.2 to 500 micrometers. Such a formulation isadministered by rapid inhalation through the nasal passage from acontainer of the powder held close to the nares.

Formulations for nasal administration may, for example, comprise fromabout as little as 0.1% (w/w) to as much as 100% (w/w) of the activeingredient, and may comprise one or more of the additional ingredientsdescribed herein. A pharmaceutical composition of the invention can beprepared, packaged, and/or sold in a formulation for buccaladministration. Such formulations may, for example, be in the form oftablets, and/or lozenges made using conventional methods, and maycontain, for example, 0.1 to 20% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.Alternately, formulations for buccal administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.1 to about 200 nanometers,and may further comprise one or more of the additional ingredientsdescribed herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation for ophthalmic administration. Suchformulations may, for example, be in the form of eye drops including,for example, a 0.1/1.0% (w/w) solution and/or suspension of the activeingredient in an aqueous or oily liquid carrier. Such drops may furthercomprise buffering agents, salts, and/or one or more other of theadditional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are contemplated asbeing within the scope of this invention.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular subject or organism will dependupon a variety of factors including the disease being treated and theseverity of the disorder; the activity of the specific active ingredientemployed; the specific composition employed; the age, body weight,general health, sex and diet of the subject; the time of administration,route of administration, and rate of excretion of the specific activeingredient employed; the duration of the treatment; drugs used incombination or coincidental with the specific active ingredientemployed; and like factors well known in the medical arts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration).

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound(s), mode ofadministration, and the like. The desired dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the desired dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations). An effective amount may be included in a single dose(e.g., single oral dose) or multiple doses (e.g., multiple oral doses).In certain embodiments, when multiple doses are administered to asubject or applied to a tissue or cell, any two doses of the multipledoses include different or substantially the same amounts of a compounddescribed herein. In certain embodiments, when multiple doses areadministered to a subject or applied to a tissue or cell, the frequencyof administering the multiple doses to the subject or applying themultiple doses to the tissue or cell is three doses a day, two doses aday, one dose a day, one dose every other day, one dose every third day,one dose every week, one dose every two weeks, one dose every threeweeks, or one dose every four weeks. In certain embodiments, thefrequency of administering the multiple doses to the subject or applyingthe multiple doses to the tissue or cell is one dose per day. In certainembodiments, the frequency of administering the multiple doses to thesubject or applying the multiple doses to the tissue or cell is twodoses per day. In certain embodiments, the frequency of administeringthe multiple doses to the subject or applying the multiple doses to thetissue or cell is three doses per day. In certain embodiments, whenmultiple doses are administered to a subject or applied to a tissue orcell, the duration between the first dose and last dose of the multipledoses is one day, two days, four days, one week, two weeks, three weeks,one month, two months, three months, four months, six months, ninemonths, one year, two years, three years, four years, five years, sevenyears, ten years, fifteen years, twenty years, or the lifetime of thesubject, tissue, or cell. In certain embodiments, the duration betweenthe first dose and last dose of the multiple doses is three months, sixmonths, or one year. In certain embodiments, the duration between thefirst dose and last dose of the multiple doses is the lifetime of thesubject, tissue, or cell. In certain embodiments, a dose (e.g., a singledose, or any dose of multiple doses) described herein includesindependently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg,between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, orbetween 1 g and 10 g, inclusive, of a compound described herein. Incertain embodiments, a dose described herein includes independentlybetween 1 mg and 3 mg, inclusive, of a compound described herein. Incertain embodiments, a dose described herein includes independentlybetween 3 mg and 10 mg, inclusive, of a compound described herein. Incertain embodiments, a dose described herein includes independentlybetween 10 mg and 30 mg, inclusive, of a compound described herein. Incertain embodiments, a dose described herein includes independentlybetween 30 mg and 100 mg, inclusive, of a compound described herein.

In certain embodiments, a dose described herein is a dose to an adulthuman whose body weight is 70 kg. In certain embodiments, an effectiveamount of a compound for administration one or more times a day to a 70kg adult human may comprise about 0.0001 mg to about 3000 mg, about0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mgto about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of acompound per unit dosage form.

In certain embodiments, the compounds of Formula (I) may be at dosagelevels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg,from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kgto about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg,from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionalpharmaceutical agents. The compounds or compositions can be administeredin combination with additional pharmaceutical agents that improve theirbioavailability, reduce and/or modify their metabolism, inhibit theirexcretion, and/or modify their distribution within the body. It willalso be appreciated that the therapy employed may achieve a desiredeffect for the same disorder, and/or it may achieve different effects.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional pharmaceutical agents,which may be useful as, e.g., combination therapies. Pharmaceuticalagents include therapeutically active agents. Pharmaceutical agents alsoinclude prophylactically active agents. Each additional pharmaceuticalagent may be administered at a dose and/or on a time schedule determinedfor that pharmaceutical agent. The additional pharmaceutical agents mayalso be administered together with each other and/or with the compoundor composition described herein in a single dose or administeredseparately in different doses. The particular combination to employ in aregimen will take into account compatibility of the inventive compoundwith the additional pharmaceutical agents and/or the desired therapeuticand/or prophylactic effect to be achieved. In general, it is expectedthat the additional pharmaceutical agents in combination be utilized atlevels that do not exceed the levels at which they are utilizedindividually. In some embodiments, the levels utilized in combinationwill be lower than those utilized individually.

Exemplary additional pharmaceutical agents include, but are not limitedto, anti-proliferative agents, anti-cancer agents, anti-diabetic agents,anti-inflammatory agents, immunosuppressant agents, and a pain-relievingagent. Pharmaceutical agents include small organic molecules such asdrug compounds (e.g., compounds approved by the U.S. Food and DrugAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins, and cells. In certain embodiments, the additionalpharmaceutical agent is selected from the group consisting of cytotoxicagents, epigenetic or transcriptional modulators (e.g., DNAmethyltransferase inhibitors, histone deacetylase inhibitors (HDACinhibitors), lysine methyltransferase inhibitors), antimitotic drugs(e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g.,estrogen receptor modulators and androgen receptor modulators), cellsignaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors),modulators of protein stability (e.g., proteasome inhibitors), Hsp90inhibitors, glucocorticoids, all-trans retinoic acids, and other agentsthat promote differentiation. In certain embodiments, the compoundsdescribed herein or pharmaceutical compositions can be administered incombination with an anti-cancer therapy including, but not limited to,surgery, radiation therapy, transplantation (e.g., stem celltransplantation, bone marrow transplantation), immunotherapy, andchemotherapy.

Also encompassed by the invention are kits (e.g., pharmaceutical packs).The inventive kits may be useful for preventing and/or treating aproliferative disease (e.g., cancer (e.g., leukemia, lymphoma, melanoma,multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, braincancer, neuroblastoma, lung cancer), benign neoplasm, angiogenesis,inflammatory disease, autoinflammatory disease, or autoimmune disease).The kits provided may comprise an inventive pharmaceutical compositionor compound and a container (e.g., a vial, ampule, bottle, syringe,and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of an inventive pharmaceutical composition or compound. Insome embodiments, the inventive pharmaceutical composition or compoundprovided in the container and the second container are combined to formone unit dosage form.

Thus, in one aspect, provided are kits including a first containercomprising a compound described herein, or a pharmaceutically acceptablesalt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,isotopically labeled derivative, and prodrug thereof, or apharmaceutical composition thereof. In certain embodiments, the kit ofthe invention includes a first container comprising a compound describedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof. In certain embodiments, the kits areuseful in preventing and/or treating a proliferative disease in asubject. In certain embodiments, the kits further include instructionsfor administering the compound, or a pharmaceutically acceptable salt,solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,isotopically labeled derivative, and prodrug thereof, or apharmaceutical composition thereof, to a subject to prevent and/or treata proliferative disease.

Methods of Treatment and Uses

The present invention also provides methods for the treatment orprevention of a proliferative disease (e.g., cancer, benign neoplasm,angiogenesis, inflammatory disease, autoinflammatory disease, orautoimmune disease) or an infectious disease (e.g., a viral disease) ina subject.

In certain embodiments, the subject being treated is a mammal. Incertain embodiments, the subject is a human. In certain embodiments, thesubject is a domesticated animal, such as a dog, cat, cow, pig, horse,sheep, or goat. In certain embodiments, the subject is a companionanimal such as a dog or cat. In certain embodiments, the subject is alivestock animal such as a cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a zoo animal. In another embodiment, thesubject is a research animal such as a rodent, dog, or non-humanprimate. In certain embodiments, the subject is a non-human transgenicanimal such as a transgenic mouse or transgenic pig.

The proliferative disease to be treated or prevented using the compoundsof Formula (I) may be associated with overexpression of a kinase. Theproliferative disease to be treated or prevented using the compounds ofFormula (I) may be associated with aberrant activity of a kinase. Incertain embodiments, the kinase is a lipid kinase. In certainembodiments, the lipid kinase is a PIP kinase. In certain embodiments,the PIPK is PIP4K, catalyzing phosphorylation of lipidphosphatidylinositol-5-phosphate (PI-5-P) at the 4-position to generatephosphatidylinositol-4,5-bisphosphate (PI-4,5-P₂). In some embodiments,the PP4K is class I PIP4K, i.e. PIP4K1. In some embodiments, the PIP4Kis class II PIP4K, i.e. PIP4K2. In some embodiments, the PIP4K2 isPIP4K2A protein. In some embodiments, the PIP4K2 is PIP4K2B protein. Insome embodiments, the PIP4K2 is PIP4K2C protein.

In certain embodiments, the kinase is a protein kinase. In certainembodiments, the protein kinase is a cyclin-dependent kinase (CDK). Theprocess of eukaryotic cell division may be broadly divided into a seriesof sequential phases termed G1, S, G2, and M. Correct progressionthrough the various phases of the cell cycle has been shown to becritically dependent upon the spatial and temporal regulation of afamily of proteins known as cyclin dependent kinases (CDKs) and adiverse set of their cognate protein partners termed cyclins. CDKs areCDC2 (also known as CDK1) homologous serine-threonine kinase proteinsthat are able to utilize ATP as a substrate in the phosphorylation ofdiverse polypeptides in a sequence-dependent context. Cyclins are afamily of proteins characterized by a homology region, containingapproximately 100 amino acids, termed the “cyclin box” which is used inbinding to, and defining selectivity for, specific CDK partner proteins.In certain embodiments, the CDK is CDK7. In certain embodiments, the CDKis CDK12. In certain embodiments, the CDK is CDK13.

In certain embodiments, a proliferative disease may be associated withaberrant activity of a CDK (e.g., CDK7). Aberrant activity of a CDK(e.g., CDK7) may be an elevated and/or an inappropriate activity of theCDK. Deregulation of cell cycle progression is a characteristic of aproliferative disease, and a majority of proliferative diseases haveabnormalities in some component of CDK (e.g., CDK7) activity, frequentlythrough elevated and/or inappropriate CDK activation. Inhibition of thecatalytic activity of CDK7 would be expected to inhibit cell cycleprogression by blocking the phosphorylation of cell cycle CDKs, andwould additionally inhibit transcription of effectors of cell division.In certain embodiments, CDK7 is not overexpressed, and the activity ofCDK7 is elevated and/or inappropriate. In certain other embodiments,CDK7 is overexpressed, and the activity of CDK7 is elevated and/orinappropriate. The compounds of Formula (I), and pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, co-crystals,tautomers, stereoisomers, isotopically labeled derivatives, prodrugs,and compositions thereof, may inhibit the activity of CDK7 and be usefulin treating and/or preventing proliferative diseases.

In other embodiments, the proliferative disease to be treated orprevented using the compounds of Formula (I) will typically beassociated with aberrant activity of CDK12. Aberrant activity of CDK12may be an elevated and/or an inappropriate (e.g., abnormal) activity ofCDK12. In certain embodiments, CDK12 is not overexpressed, and theactivity of CDK12 is elevated and/or inappropriate. In certain otherembodiments, CDK12 is overexpressed, and the activity of CDK12 iselevated and/or inappropriate. The compounds of Formula (I), andpharmaceutically acceptable salts, solvates, hydrates, tautomers,stereoisomers, isotopically labeled derivatives, and compositionsthereof, may inhibit the activity of CDK12 and be useful in treatingand/or preventing proliferative diseases.

In other embodiments, the proliferative disease to be treated orprevented using the compounds of Formula (I) will typically beassociated with aberrant activity of CDK13. Aberrant activity of CDK13may be an elevated and/or an inappropriate (e.g., abnormal) activity ofCDK13. In certain embodiments, CDK13 is not overexpressed, and theactivity of CDK13 is elevated and/or inappropriate. In certain otherembodiments, CDK13 is overexpressed, and the activity of CDK13 iselevated and/or inappropriate. The compounds of Formula (I), andpharmaceutically acceptable salts, solvates, hydrates, tautomers,stereoisomers, isotopically labeled derivatives, and compositionsthereof, may inhibit the activity of CDK13 and be useful in treatingand/or preventing proliferative diseases.

In certain embodiments, the proliferative disease to be treated orprevented using the compounds of Formula (I) is cancer. All types ofcancers disclosed herein or known in the art are contemplated as beingwithin the scope of the invention. In some embodiments, the cancer hasone or more mutations. In certain embodiments, the cancer has EGFRmutation. In certain embodiments, the cancer has TP53 mutation. Incertain embodiments, the cancer has loss of TP53 mutation. In certainembodiments, the cancer has KRAS mutation. In certain embodiments, thecancer has ALK mutation. In certain embodiments, the proliferativedisease is a cancer associated with dependence on BCL-2 anti-apoptoticproteins (e.g., MCL-1 and/or XIAP). In certain embodiments, theproliferative disease is a cancer associated with overexpression of MYC(a gene that codes for a transcription factor). In certain embodiments,the proliferative disease is a hematological malignancy. In certainembodiments, the proliferative disease is a blood cancer. In certainembodiments, the proliferative disease is a hematological malignancy. Incertain embodiments, the proliferative disease is leukemia. In certainembodiments, the proliferative disease is chronic lymphocytic leukemia(CLL). In certain embodiments, the proliferative disease is acutelymphoblastic leukemia (ALL). In certain embodiments, the proliferativedisease is T-cell acute lymphoblastic leukemia (T-ALL). In certainembodiments, the proliferative disease is chronic myelogenous leukemia(CML). In certain embodiments, the proliferative disease is acutemyelogenous leukemia (AML). In certain embodiments, the proliferativedisease is acute monocytic leukemia (AMoL). In certain embodiments, theproliferative disease is lymphoma. In certain embodiments, theproliferative disease is a Hodgkin's lymphoma. In certain embodiments,the proliferative disease is a non-Hodgkin's lymphoma. In certainembodiments, the proliferative disease is multiple myeloma. In certainembodiments, the proliferative disease is melanoma. In certainembodiments, the proliferative disease is breast cancer. In certainembodiments, the proliferative disease is triple-negative breast cancer(TNBC). In certain embodiments, the proliferative disease is a bonecancer. In certain embodiments, the proliferative disease isosteosarcoma. In certain embodiments, the proliferative disease isEwing's sarcoma. In some embodiments, the proliferative disease is abrain cancer. In some embodiments, the proliferative disease isneuroblastoma. In some embodiments, the proliferative disease is a lungcancer. In some embodiments, the lung cancer has one or more mutations.In certain embodiments, the lung cancer has EGFR mutation. In certainembodiments, the lung cancer has TP53 mutation. In certain embodiments,the lung cancer has loss of TP53 mutation. In certain embodiments, thelung cancer has KRAS mutation. In certain embodiments, the lung cancerhas ALK mutation. In some embodiments, the proliferative disease issmall cell lung cancer (SCLC). In some embodiments, the proliferativedisease is non-small cell lung cancer. In some embodiments, theproliferative disease is a benign neoplasm. All types of benignneoplasms disclosed herein or known in the art are contemplated as beingwithin the scope of the invention. In some embodiments, theproliferative disease is associated with angiogenesis. All types ofangiogenesis disclosed herein or known in the art are contemplated asbeing within the scope of the invention. In certain embodiments, theproliferative disease is an inflammatory disease. All types ofinflammatory diseases disclosed herein or known in the art arecontemplated as being within the scope of the invention. In certainembodiments, the inflammatory disease is rheumatoid arthritis. In someembodiments, the proliferative disease is an autoinflammatory disease.All types of autoinflammatory diseases disclosed herein or known in theart are contemplated as being within the scope of the invention. In someembodiments, the proliferative disease is an autoimmune disease. Alltypes of autoimmune diseases disclosed herein or known in the art arecontemplated as being within the scope of the invention.

In certain embodiments, the infectious disease to be treated orprevented using the compounds of Formula (I) is a viral disease. Suchviral infections are described in U.S. Provisional Patent Application,U.S. Ser. No. 61/622,828, filed Apr. 11, 2012, and international PCTapplication, PCT/US2013/032488, filed Mar. 15, 2013 and published onOct. 17, 2011, each of which is incorporated herein in its entirety byreference.

The cell described herein may be an abnormal cell. The cell may be invitro or in vivo. In certain embodiments, the cell is a proliferativecell. In certain embodiments, the cell is a blood cell. In certainembodiments, the cell is a lymphocyte. In certain embodiments, the cellis a B-cell. In certain embodiments, the cell is a T-cell. In certainembodiments, the cell is a cancer cell. In certain embodiments, the cellis a leukemia cell. In certain embodiments, the cell is a CLL cell. Incertain embodiments, the cell is a melanoma cell. In certainembodiments, the cell is a multiple myeloma cell. In certainembodiments, the cell is a benign neoplastic cell. In certainembodiments, the cell is an endothelial cell. In certain embodiments,the cell is an immune cell.

In another aspect, the present invention provides methods of modulatingthe activity of a kinase (e.g. a lipid kinase such as PIPK (e.g.PIP4K2A, PIP4K2B, or PIP4K2C protein) enzyme or a protein kinase such asCDK (e.g., CDK7, CDK1, CDK2, CDK5, CDK8, CDK9, CDK12, CDK13) enzyme) ina biological sample or subject. In certain embodiments, the activity ofthe kinase is aberrant activity of the kinase. In certain embodiments,the inhibition of the activity of the kinase is irreversible. In otherembodiments, the inhibition of the activity of the kinase is reversible.In certain embodiments, the methods of inhibiting the activity of thekinase include attaching a compound of Formula (I) to the kinase.

Also provided in the present invention are methods of inhibitingtranscription in a biological sample or subject.

The present invention also provides methods of inhibiting cell growth ina biological sample or subject.

In certain embodiments, the methods described herein includeadministering to a subject or contacting a biological sample with aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, or prodrug thereof, or apharmaceutical composition thereof. In certain embodiments, the methodsdescribed herein include administering to a subject or contacting abiological sample with an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof. In certain embodiments, the compound is contactedwith a biological sample. In certain embodiments, the compound isadministered to a subject.

In certain embodiments, the compound is administered in combination withone or more additional pharmaceutical agents described herein. Theadditional pharmaceutical agent may be an anti-proliferative agent. Incertain embodiments, the additional pharmaceutical agent is ananti-cancer agent. In certain embodiments, the additional pharmaceuticalagent is an anti-leukemia agent. In certain embodiments, the additionalpharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF(doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON(nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX(busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicinhydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine),CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN(cyclophosphamide), ERWINAZE (Asparaginase Erwinia chrysanthemi),FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS(methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate),Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib),LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristinesulfate liposome), METHOTREXATE LPF (methorexate), MEXATE(methotrexate), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride,MUSTARGEN (mechlorethamine hydrochloride), MYLERAN (busulfan), NEOSAR(cyclophosphamide), ONCASPAR (Pegaspargase), PURINETHOL(mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicinhydrochloride), SPRYCEL (dasatinib), SYNRIBO (omacetaxinemepesuccinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), TREANDA(bendamustine hydrochloride), TRISENOX (arsenic trioxide), VINCASAR PFS(vincristine sulfate), ZYDELIG (idelalisib), or a combination thereof.In certain embodiments, the additional pharmaceutical agent is ananti-lymphoma agent. In certain embodiments, the additionalpharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC,ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicinhydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN(chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine),BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR(tositumomab and iodine 1131 tositumomab), BICNU (carmustine), BLENOXANE(bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide),COPP, COPP-ABV, CVP, CYTOXAN (cyclophosphamide), DEPOCYT (liposomalcytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX (methotrexate), FOLEXPFS (methotrexate), FOLOTYN (pralatrexate), HYPER-CVAD, ICE, IMBRUVICA(ibrutinib), INTRON A (recombinant interferon alfa-2b), ISTODAX(romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil),Lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF(methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP,MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR(cyclophosphamide), OEPA, ONTAK (denileukin diftitox), OPPA, R-CHOP,REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V, TREANDA(bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate),VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCASAR PFS(vincristine sulfate), ZEVALIN (ibritumomab tiuxetan), ZOLINZA(vorinostat), ZYDELIG (idelalisib), or a combination thereof. In certainembodiments, the additional pharmaceutical agent is ananti-myelodysplasia agent. In certain embodiments, the additionalpharmaceutical agent is REVLIMID (lenalidomide), DACOGEN (decitabine),VIDAZA (azacitidine), CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin),CERUBIDINE (daunorubicin), or a combination thereof.

In certain embodiments, the additional pharmaceutical agent is ananti-macroglobulinemia agent.In certain embodiments, the additional pharmaceutical agent is LEUKERAN(chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine),LEUSTATIN (cladribine), or a combination thereof. In certainembodiments, the additional pharmaceutical agent is ABITREXATE(methotrexate), ABRAXANE (paclitaxel albumin-stabilized nanoparticleformulation), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicin hydrochloride),ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITOR DISPERZ(everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA(pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane),AVASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU (carmustine),BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPOX,CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine),CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicinhydrochloride), CERVARIX (recombinant HPV bivalent vaccine), CLAFEN(cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN(dactinomycin), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U(cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine),DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), DOXORUBICINHYDROCHLORIDE, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME(dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicinhydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE(vismodegib), ETOPOPHOS (etoposide phosphate), EVACET (doxorubicinhydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant),FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX(methotrexate), FOLEX PFS (methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB,FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinanthuman papillomavirus (HPV) quadrivalent vaccine), GEMCITABINE-CISPLATIN,GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF(afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustineimplant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab),HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM(ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferonalfa-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinibphosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine),KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicinhydrochloride liposome), LUPRON (leuprolide acetate), LUPRON DEPOT(leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate), LUPRONDEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolideacetate), MEGACE (megestrol acetate), MEKINIST (trametinib),METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE(methotrexate), MEXATE-AQ (methotrexate), MITOXANTRONE HYDROCHLORIDE,MITOZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN(mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR(azacitidine), NAVELBINE (vinorelbine tartrate), NEOSAR(cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifencitrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT(carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferonalfa-2b), PEMETREXED DISODIUM, PERJETA (pertuzumab), PLATINOL(cisplatin), PLATINOL-AQ (cisplatin), POMALYST (pomalidomide),prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE(sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicinhydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT(sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT(siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib),TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA(nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR(temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL(temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinibditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate),VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide),VIADUR (leuprolide acetate), VIDAZA (azacitidine), VINCASAR PFS(vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN(leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine),XELOX, XGEVA (denosumab), XOFIGO (radium 223 dichloride), XTANDI(enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF(vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid),ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), or a combinationthereof. In certain embodiments, the additional pharmaceutical agent isa histone deacetylase inhibitor. In certain embodiments, the histonedeacetylase inhibitor is a hydroxamic acid such as Vorinostat (SAHA),ITF2357, or PXD-101, a cyclic peptide such as depsipeptide, a benzamidesuch as MS-275, or an aliphatic acid such as valproic acid or AN-9.

In certain embodiments, the additional pharmaceutical agent is aninhibitor of a lipid kinase. In certain embodiments, the additionalpharmaceutical agent is an inhibitor of a PIP4K. In certain embodiments,the additional pharmaceutical agent is an inhibitor of a PIP4K2. Incertain embodiments, the additional pharmaceutical agent is an inhibitorof a PIP4K2A. In certain embodiments, the additional pharmaceuticalagent is an inhibitor of a PIP4K2B. In certain embodiments, theadditional pharmaceutical agent is an inhibitor of a PIP4K2C. In certainembodiments, the additional pharmaceutical agent is an inhibitor of aprotein kinase. In certain embodiments, the additional pharmaceuticalagent is an inhibitor of a CDK. In certain embodiments, the additionalpharmaceutical agent is an inhibitor of CDK7. In certain embodiments,the additional pharmaceutical agent is an inhibitor of CDK12. In certainembodiments, the additional pharmaceutical agent is an inhibitor ofCDK13. In certain embodiments, the additional pharmaceutical agent isflavopiridol, triptolide, SNS-032 (BMS-387032), PHA-767491, PHA-793887,BS-181, (S)-CR8, (R)-CR8, or NU6140. In certain embodiments, theadditional pharmaceutical agent is an inhibitor of a mitogen-activatedprotein kinase (MAPK). In certain embodiments, the additionalpharmaceutical agent is an inhibitor of a glycogen synthase kinase 3(GSK3). In certain embodiments, the additional pharmaceutical agent isan inhibitor of an AGC kinase. In certain embodiments, the additionalpharmaceutical agent is an inhibitor of a CaM kinase. In certainembodiments, the additional pharmaceutical agent is an inhibitor of acasein kinase 1. In certain embodiments, the additional pharmaceuticalagent is an inhibitor of a STE kinase. In certain embodiments, theadditional pharmaceutical agent is an inhibitor of a tyrosine kinase. Incertain embodiments, the additional pharmaceutical agent is an inhibitorof one or more protein kinases selected from the group consisting ofIRAK1, IRAK4, BMX, and PI3K. In certain embodiments, the additionalpharmaceutical agent is an inhibitor of one or more protein kinasesselected from the group consisting of BUB1B, CDK2, CDK9, CHEK2, FGR,HIPK4, PRKCQ, RET, SRC, or MELK. In certain embodiments, the additionalpharmaceutical agent is an inhibitor of one or more protein kinasesselected from the group consisting of ABL, ARG, BLK, CSK, EphB1, EphB2,FGR, FRK, FYN, SRC, YES, LCK, LYN, MAP2K5, NLK, p38a, SNRK, and TEC. Incertain embodiments, the additional pharmaceutical agent is an inhibitorof one or more protein kinases selected from the group consisting ofABL1(H396P)-phosphorylated, ABL1-phosphorylated, BLK, EPHA4, EPHB2,EPHB3, EPHB4, FGR, JAK3 (JH1domain-catalytic), KIT, KIT(L576P),KIT(V559D), PDGFRB, SRC, YES, ABL1(H396P)-nonphosphorylated, ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, FRK, LYN,ABL1(Q252H)-nonphosphorylated, DDR1, EPHB1, ERBB4, p38-alpha, ABL2,ABL1(Q252H)-phosphorylated, SIK, EPHA8, MEK5,ABL1(E255K)-phosphorylated, ABL1(F317L)-nonphosphorylated, FYN, LCK,EPHA2, ABL1(M351T)-phosphorylated, TXK, EGFR(L858R), EGFR(L861Q), ERBB2,ERBB3, EPHA5, ABL1(F317I)-nonphosphorylated, EGFR(L747-E749del, A750P),CSK, EPHA1, ABL1(F317L)-phosphorylated, BRAF(V600E), EGFR,KIT-autoinhibited, and EGFR(E746-A750del). In certain embodiments, theadditional pharmaceutical agent is an inhibitor of one or more proteinkinases selected from the group consisting ofABL1(F317L)-nonphosphorylated, ABL1(H396P)-nonphosphorylated,ABL1(H396P)-phosphorylated, ABL1-phosphorylated, BLK, EPHA4, EPHB2,EPHB3, EPHB4, JAK3(JH1domain-catalytic), KIT, KIT(L576P), KIT(V559D),LYN, PDGFRB, SRC, YES, ABL1-nonphosphorylated,ABL1(Y253F)-phosphorylated, ERBB3, FGR, FRK, p38-alpha,ABL1(F317I)-nonphosphorylated, DDR1, EPHA2, ABL1(Q252H)-phosphorylated,MEK5, ABL1(Q252H)-nonphosphorylated, ABL2, FYN, EPHB1,ABL1(E255K)-phosphorylated, ABL1(F317L)-phosphorylated, EPHA1,ABL1(M351T)-phosphorylated, ERBB4, TXK, LCK, EPHA8, SIK, EPHA5,EGFR(L861Q), CSF1R-autoinhibited, BRAF(V600E), BRK, CSK, KIT(D816V),KIT-autoinhibited, EGFR(L747-T751del, Sins), EGFR(L858R),EGFR(L747-E749del, A750P), and CSF1R. In certain embodiments, theadditional pharmaceutical agent is an anti-angiogenesis agent,anti-inflammatory agent, immunosuppressant, anti-bacterial agent,anti-viral agent, cardiovascular agent, cholesterol-lowering agent,anti-diabetic agent, anti-allergic agent, pain-relieving agent, or acombination thereof. In certain embodiments, the compounds describedherein or pharmaceutical compositions can be administered in combinationwith an anti-cancer therapy including, but not limited to,transplantation (e.g., bone marrow transplantation, stem celltransplantation), surgery, radiation therapy, immunotherapy, andchemotherapy.

Another aspect of the invention relates to methods of screening alibrary of compounds to identify one or more compounds that are usefulin the treatment of a proliferative disease, in inhibiting a kinase(e.g., PIPK or CDK (e.g CDK7, CDK12, CDK13) enzyme), in inhibiting cellgrowth. In certain embodiments, the library of compounds is a library ofcompounds of Formula (I). The methods of screening a library includeproviding at least two different compounds of Formula (I), orpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,or prodrugs thereof, or pharmaceutical compositions thereof; andperforming at least one assay using the different compounds of Formula(I), or pharmaceutically acceptable salts, solvates, hydrates,polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeledderivatives, or prodrugs thereof, or pharmaceutical compositionsthereof, to detect one or more characteristics associated with theproliferative disease. In certain embodiments, the methods of screeninga library include providing at least two different compounds of Formula(I), or pharmaceutically acceptable salts thereof, or pharmaceuticalcompositions thereof; and performing at least one assay using thedifferent compounds of Formula (I), or pharmaceutically acceptable saltsthereof, or pharmaceutical compositions thereof, to detect one or morecharacteristics associated with the proliferative disease. Thecharacteristic to be detected may be a desired characteristic associatedwith the proliferative disease. In certain embodiments, the desiredcharacteristic is anti-proliferation. In certain embodiments, thedesired characteristic is anti-cancer. In certain embodiments, thedesired characteristic is inhibition of a kinase. In certainembodiments, the desired characteristic is inhibition of a lipid kinase.In certain embodiments, the desired characteristic is inhibition ofPIPK. In certain embodiments, the desired characteristic is inhibitionof PIP4K. In certain embodiments, the desired characteristic isinhibition of PIP4K2. In certain embodiments, the desired characteristicis inhibition of PIP4K2A. In certain embodiments, the desiredcharacteristic is inhibition of PIP4K2B. In certain embodiments, thedesired characteristic is inhibition of PIP4K2C. In certain embodiments,the desired characteristic is inhibition of a protein kinase. In certainembodiments, the desired characteristic is inhibition of CDK. In certainembodiments, the desired characteristic is inhibition of CDK7. Incertain embodiments, the desired characteristic is inhibition of CDK12.In certain embodiments, the desired characteristic is inhibition ofCDK13. In certain embodiments, the desired characteristic isdown-regulation of a kinase such as PIPK or CDK.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Synthesis of the Compounds

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.See, e.g., Scheme 1 below. It will be appreciated that where typical orpreferred process conditions (i.e., reaction temperatures, times, moleratios of reactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvents used, butsuch conditions can be determined by those skilled in the art by routineoptimization procedures. Additionally, as will be apparent to thoseskilled in the art, conventional protecting groups may be necessary toprevent certain functional groups from undergoing undesired reactions.The choice of a suitable protecting group for a particular functionalgroup as well as suitable conditions for protection and deprotection arewell known in the art. For example, numerous protecting groups, andtheir introduction and removal, are described in Greene et al.,Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York,1991, and references cited therein.

Example 1. The synthesis of(E)-N-(3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide

Compound 8 was prepared according to the method described in Scheme 1 orthe method described below.

5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (Compound 1)

Compound numbers 1 to 8 recited in Example 1 apply only to Example 1,and FIGS. 2, 3A to 3D, 4A, 4B, 5A, and 5B. To a solution of5-bromo-1H-pyrrolo[2,3-b]pyridine (10 g, 50.7 mmol) in pyridine (100 mL)was added benzenesulfonyl chloride (44.8 g, 253.8 mmol). The resultingmixture was heated to 80° C. for 4h and then concentrated under vacuum.The residue was diluted with EtOAc (300 mL). The pH of the solution wasadjusted to 3 with 1M HCl and the resulting mixture was washed withNaHCO₃ and water. The organic layer washed with water and brine, dried(Na₂SO₄), and concentrated. The residue was purified by a silica gelcolumn to afford (15 g, 88%) of the title compound (1) as a slightlyyellow solid. MS m/z 339.19 [M+H]⁺.

1-(phenylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(Compound 2)

To a solution of 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]Pyridine(15 g, 44.5 mmol) in 1,4-dioxane (100 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(13.5 g, 53.4mmol), Pd(dppf)Cl₂(1.6 g, 2.2 mmol) and KOAc (6.5g, 66.7 mmmol). Thereaction mixture was heated to 100° C. for 12h under the N₂. Theresulting mixture was concentrated to dryness. The residue was purifiedby a silica gel column to afford (14 g, 82%) of the title compound (2)as a slightly yellow solid. MS m/z 385.26 [M+H]⁺.

5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(Compound 3)

To a solution of1-(phenylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(1 g, 2.6 mmol) in MeCN and H₂O(20 mL, 4/1, v/v) was added4,6-dichloropyrimidine (0.38 g, 2.6 mmol), NaHCO₃(0.21 g, 2.6 mmol) andPd(PPh₃)₂C₂(91 mg, 0.013 mmol). The reaction mixture was heated to 90°C. for 12h under the N₂. Then the resulting mixture was diluted withEtOAc (100 mL) at room temperature, washed with water and brine anddried (Na₂SO₄). The residue was purified by a silica gel column toafford (0.8 g, 83%) of the title compound (3) as a slightly yellowsolid. MS m/z 371.81 [M+H]⁺.

N¹-(6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)benzene-1,3-diamine(Compound 4)

To a solution of5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo-[2,3-b]pyridine(0.5 g, 1.3 mmol) in NMP (10 mL) was added benzene-1,3-diamine (0.72 g,6.7 mmol). The reaction mixture was heated to 150° C. for 5h. Thenresulting mixture was diluted with EtOAc (150 mL) at room temperature,washed with water and brine, dried (Na₂SO₄). The residue was purified bya silica gel column to afford (0.3 g, 50%) of the title compound (4) asa slightly yellow solid. MS m/z 443.49 [M+H]⁺.

4-nitro-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(Compound 5)

To a solution ofN¹-(6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)benzene-1,3-diamine(0.3 g, 0.67 mmol) in DCM (10 mL) was added TEA (83.0 mg, 0.81 mmol) and4-nitrobenzoyl chloride (151 mg, 0.81 mmol) at 0° C. during 3 min. Thenresulting mixture was diluted with DCM (50 mL), washed with water andbrine, dried (Na₂SO₄). The residue was purified by a silica gel columnto afford the title compound (5) (0.3 g, 75.0%) as a slightly yellowsolid. MS m/z 592.60 [M+H]⁺.

4-amino-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(Compound 6)

To a solution of4-nitro-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(0.3 g, 0.50 mmol) in MeOH (10 mL) was added 10% Pd/C (50 mg). Thereaction mixture was stirred at room temperature for 2h under a balloonof H₂. Then resulting mixture was then filtered through a short pad ofCELITE. The filtrate was concentrated to afford the title compound (6)(0.24 g, 84%) as a slightly yellow solid. MS m/z 562.60 [M+H]⁺.

(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(Compound 7)

To a solution of4-amino-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(0.24 g, 0.42 mmol) in MeCN (10 mL) was added DIEA (66.7 mg, 0.51 mmol)and (E)-4-bromobut-2-enoyl chloride (12.21 mg, 0.51 mmol) at 0C during 3min. Then 2 mL of dimethylamine (4.0M in THF) was added. The reactionmixture was stirred at room temperature for 2h. Then it was concentratedand purified by a silica gel column to afford the title compound (7)(0.2 g, 71%) as a slightly yellow solid. MS m/z 673.76 [M+H]⁺.

(E)-N-(3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide(Compound 8)

To a solution of(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(0.10 g, 0.14 mmol) in 1M NaOH and 1,4-dioxane (6 mL, 1/1, v/v). Thereaction mixture was stirred at room temperature for 4 h. Then the pH ofthe solution was adjusted to 7 by 1M HCl. The resulting mixture wasconcentrated. The residue was purified by a silica gel column to affordof the title compound (6 mg, 8%) as a slightly yellow solid. MS m/z533.60 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 9.74 (s, 1H),8.92 (s, 1H), 8.73 (s, 1H), 8.62 (s, 1H), 8.20 (s, 1H), 7.99 (d, J=8.4Hz, 2H), 7.83 (d, J=8.3 Hz, 2H), 7.58 (s, 1H), 7.54 (s, 1H), 7.40 (d,J=6.5 Hz, 2H), 7.34 (d, J=7.9 Hz, 1H), 6.80 (d, J=15.4 Hz, 1H), 6.60 (s,1H), 6.36 (d, J=15.1 Hz, 1H), 3.22 (s, 2H), 2.28 (s, 6H).

Example 2. The Synthesis of THZ-CE-A-4-1

N1-(6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)cyclohexane-1,3-diamine)

Compound numbers 1 to 8 recited in Example 2 apply only to Example 2. Toa stirred suspension of5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(2.0 g, 54 mmol) in NMP, cyclohexane-1,3-diamine (0.74 g, 65 mmol) andDIEA (0.85 g, 65 mmol) was added and the solution was then heated at150° C. overnight. The solution was cooled down to room temperature andthen was diluted with 300 mL of ethyl acetate. The resulted solution waswashed with water and brine. After drying with Na₂SO₄, the solvent wasthen removed, and the product was obtained by flash chromatography withdichloromethane/methanol (50/1) as eluent (1 g, yield 42%).

4-nitro-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)cyclohexyl)benzamide

To a dichloromethane solution of free amine compound (3) (0.7 g, 1.5mmol) was added 4-nitrobenzoyl chloride (0.35 g, 1.2 equiv). Afterstirring for 1 hour, the solvent was then removed, and the crude productwas obtained by flash chromatography with dichloromethane/methanol(30/1) as eluent (0.7 g, yield 75%).

4-amino-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)cyclohexyl)benzamide

The nitro compound (5) (0.65 g, 1.1 mmol) was dissolve in ethylacetate/methanol (1:1, vol/vol, 70 ml), and the resulted suspension wastreated with Pd/C (0.15 g). After nitrogen replacement three times, thereaction mixture was stirred at the room temperature overnight. Thereaction mixture was filtered over CELITE, the solvent was then removed,and the product was obtained by flash chromatography with petroleumether/ethyl acetate/NH₃=(3/1/0.1) as eluent (0.4 g, yield 60%).

(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)cyclohexyl)benzamide

To a dichloromethane solution of free amine compound (6) (1.0 g, 1.76mmol) was added (E)-4-(dimethylamino)but-2-enoic acid hydrochloride(0.35 g, 2.11 mmol), DIEA (0.8 g, 6.16 mmol) and HATU (0.8 g, 2.11 mol).After stirring for 12 hours at room temperature, the solution wasdiluted with 100 mL of water, and extracted with dichloromethane (3×50ml). The resulted solution was washed with water and brine. After dryingwith Na₂SO₄, the solvent was then removed, and the crude product wasobtained by flash chromatography with dichloromethane/methanol(50/1-30/1) as eluent (0.5 g, yield 30%)

(E)-N-(3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)cyclohexyl)-4-(4-(dimethylamino)but-2-enamido)benzamide

The compound 8 (0.1 g) was dissolved in 1,4-dioxane (10.0 mL) and 1MNaOH solution (3.0 mL). The solution was stirred at room temperature for6 hours and then extracted with chloroform/2-propanol (4/1, vol/vol, 300mL). The organic layer was washed with water, brine and dried overNa₂SO₄, the solvent was then removed, and the product was obtained byflash chromatography with dichloromethane/methanol (10/1-5/1) as eluent(10 mg, yield 10%). M/Z 539.28 [M+H]⁺.

Example 3. The Synthesis of THZ-CE-A-4-2

3-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole

Compound numbers 1 to 6 recited in Example 3 apply only to Example 3. Toa stirred suspension of 3-bromo-1-(phenylsulfonyl)-1H-indole (5.0 g,14.87 mmol) in THF (50 mL) was added n-BuLi (2.5 M, 13 mL) at −98° C.and stirred for 5 minutes. Triisopropyl borate (3.37 g, 17.85 mmol) wasthen added dropwise at the same temperature. After 5 minutes, thereaction was quenched with aqueous HCl (10%), and the pH was adjusted to6-7 with Na₂CO₃ (3.6 g, 29.74 mmol), andtetrakis(triphenylphosphine)platinum (1 g) and 4,6-dichloropyrimidine(2.44 g, 16.36 mmol) were added directly, and the solution was refluxedovernight under nitrogen. Ethyl acetate and water were added, and thereaction mixture was filtered over CELITE. The ethyl acetate layer wasdried by Na₂SO₄, the solvent was then removed, and the product wasobtained by flash chromatography with petroleumether/dichloromethane=(1/2) as eluent (2.8 g, yield 51%).

N¹-(6-(1-(phenylsulfonyl)-1H-indol-3-yl) pyrimidin-4-yl)benzene-1,3-diamine

3-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (2) (1.4 g, 3.78mmol) and benzene-1,3-diamine (0.82 g, 2.0 equiv) was dissolved in 30 mLof NMP. DIEA (0.51 g, 3.89 mmol) was added, and then the solution washeated at 150° C. overnight. The solution was cooled down to roomtemperature and was diluted with 300 mL of ethyl acetate. The resultedsolution was washed with water and brine. After drying with Na₂SO₄, thesolvent was then removed, and the product was obtained by flashchromatography with dichloromethane/methanol (10/1) as eluent (1.6 g,yield 95%).

4-nitro-N-(3-((6-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-4-yl)amino)phenyl)benzamide

To a pyridine solution of free amine compound (3) (1.6 g, 3.62 mmol) wasadded 4-nitrobenzoyl chloride (0.74 g, 1.2 equiv). After stirring for 3hours at 80° C., The solution was cooled down to room temperature andthen was diluted with 100 mL of water and extracted with ethyl acetate(3×100 mL). The resulted solution was washed with water and brine. Afterdrying with Na₂SO₄, the solvent was then removed, and the crude productwas used to the next step directly.

4-amino-N-(3-((6-(1-(phenysulfonyl)-1H-indol-3-yl)pyrimidin-4-yl)amino)phenyl)benzamide

The compound (4) (2 g, 3.38 mmol) was dissolve in ethyl acetate/methanol(4:1, vol/vol, 70 ml), and the resulted suspension was treated with Pd/C(0.3 g). After nitrogen replacement three times the reaction mixture wasstirred at the room temperature overnight. The reaction mixture wasfiltered over CELITE, the solvent was then removed, and the product wasobtained by flash chromatography with petroleum ether/ethylacetate/NH₃=(3/1/0.1) as eluent (1.4 g, yield 74%)

(Z)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-4-yl)amino)phenyl)benzamide

To a solution of free amino compound (5) (1.4 g, 2.5 mmol) in driedacetonitrile (60 mL) was added N,N-Diisopropylethylamine (0.4 g, 3 mmol)and (E)-4-bromobut-2-enoyl chloride (0.55 g, 3 mmol) in dichloromethane(15 mL) at 0° C. dropwise. After stirring for 5 min, the solution ofdimethylamine (2 M, 25 mL) in THF was added, and the reaction mixturewas then stirred at the room temperature for 2 hours. The solution wasdiluted with 100 mL of water, and extracted with dichloromethane (3×100mL). The resulted solution was washed with water and brine. After dryingwith Na₂SO₄, the solvent was then removed, and the product was obtainedby flash chromatography with dichloromethane/methanol (20/1-10/1) aseluent (0.4 g, yield 24%)

(Z)—N-(3-((6-(1H-indol-3-yl)pyrimidin-4-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide

To a solution of(Z)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-(pheny-lsulfonyl)-1H-indol-3-yl)pyrimidin-4-yl)amino)phenyl)benzamide(6) (0.4g, 0.6 mmol) in 1,4-dioxane (26.0 mL), 1M NaOH solution (26.0mL) was added dropwise at 10° C. and then stirred at room temperaturefor 6 hours. Extracted with chloroform/2-propanol (4/1, vol/vol, 300mL). The organic layer was washed with water, brine and dried overNa₂SO₄, the solvent was then removed, and the product was obtained byflash chromatography with dichloromethane/methanol (20/1-10/1) as eluent(0.19 g, yield 60%). MS m/z 532.24 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ11.73 (s, 1H), 10.50 (s, 1H), 10.19 (s, 1H), 9.55 (s, 1H), 8.63 (s, 1H),8.27 (d, J=7.2 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J=2.8 Hz, 1H), 8.00 (d,J=8.7 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 7.59-7.44 (m, 2H), 7.37 (d, J=8.3Hz, 1H), 7.34-7.26 (m, 2H), 7.24-7.09 (m, 2H), 6.81 (dt, J=15.4, 6.2 Hz,1H), 6.40 (d, J=15.4 Hz, 1H), 3.37 (d, J=5.3 Hz, 2H), 2.39 (s, 6H).

Example 4. The Synthesis of THZ-CE-A-4-3

5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

Compound numbers 1 to 7 recited in Example 4 apply only to Example 4. Toa solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (50 g, 0.254 mol) inpyridine (300 mL) was added benzene sulfonyl chloride (224 g, 1.27 mol).The resulted mixture was heated at 85° C. for 4 hours and thenconcentrated under vacuum. The residue was diluted with EtOAc (1500 mL).The pH of the solution was adjusted to 3 with 1M HCl, and the resultedmixture was washed with NaHCO₃ and water. The organic layer was washedwith water and brine, dried (Na₂SO₄) and concentrated. The residue waspurified by a silica gel column to afford (85 g, 99.2%) of the titlecompound as a slightly yellow solid.

1-(phenylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

To a solution of 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(70 g, 0.208 mol) in 1,4-dioxane (560 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (63 g, 0.25mmol), Pd(dppf)Cl₂(7.5 g, 12.5 mmol), and KOAc (98 g, 0.374 mol). Theresulted mixture was heated at 100° C. for 12 hours under N₂. Theresidue was concentrated and purified by a silica gel column to afford(79.2 g, 99.0%) of the title compound as a slightly yellow solid.

5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

To a solution of1-(phenylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(60 g, 0.156 mol) in 1,4-Dioxane and H₂O (600 mL, 1/1, v/v) was added4,6-dichloropyrimidine (25.6 g, 0.172 mol), Na₂CO₃ (19.8 g, 0.187 mol),and Pd(PPh₃)₄ (9 g, 7.8 mmol). The resulted mixture was heated at 104°C. for 2.5 hours under N₂. Then it was diluted with EtOAc (1500 mL) atroom temperature, washed with water and brine, dried (Na₂SO₄), andconcentrated. The residue was purified by a silica gel column to afford(42 g, 72.6%) of the title compound as a slightly yellow solid.

N¹-(6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)benzene-1,3-diamine

To a solution of5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo-[2,3-b]pyridine(1.85 g, 5 mmol) in NMP (5 mL) was added benzene-1,3-diamine (1.1 g, 10mmol). The resulted mixture was heated at 150° C. for 8 hours. Then itwas diluted with EtOAc (300 mL) at room temperature, washed with waterand brine, dried (Na₂SO₄), and concentrated. The residue was purified bya silica gel column to afford (1 g, 46.0%) of the title compound as aslightly yellow solid.

3-nitro-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide

To a solution ofN¹-(6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)benzene-1,3-diamine(0.88 g, 2 mmol) in DCM (10 mL) was added DIEA (390 mg, 3 mmol) and3-nitrobenzoyl chloride (0.45 g, 2.4 mmol) at 0° C. for 5 min. Then itwas diluted with DCM (100 mL), washed with water and brine, dried(Na₂SO₄), and concentrated. The residue was purified by a silica gelcolumn to afford (0.8 g, 68.0%) of the title compound as a slightlyyellow solid.

3-amino-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide

To a solution of3-nitro-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(0.8 g, 1.35 mmol) in MeOH (30 mL) was added Pd/C (100 mg). The resultedmixture was stirred at room temperature for 12 hours under H₂. Then itwas filtered through a short pad of CELITE, and purified by a silica gelcolumn to afford (0.4 g, 53.0%) of the title compound as a slightlyyellow solid.

(E)-3-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide

To a solution of3-amino-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(0.4 g, 0.71 mmol) in DCM (20 mL) was added DIEA (0.2 g, 1.42 mmol) and(E)-4-bromobut-2-enoyl chloride (0.26 g, 1.42 mmol) at 0° C. for 30 min.Then it was added 2.0 M dimethylamine in THF (7 mL). The resultedmixture was stirred at room temperature for 2 hours. Then it wasconcentrated and purified by a silica gel column to afford (0.28 g,59.0%) of the title compound as a slightly yellow solid.

(E)-N-(3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)-3-(4-(dimethylamino)but-2-enamido)benzamide

A solution of(E)-3-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(0.28 g, 0.42 mmol) in 4M NaOH and 1,4-dioxane (5 mL, 1/1, v/v) wasstirred at room temperature for 4 hours. Then the pH of the solution wasadjusted to 7.0 with 1M HCl, and the resulted mixture was concentrated.The residue was purified by a silica gel column to afford (102 mg,45.5%) of the title compound as a slightly yellow solid. MS m/z 533.60[M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.32 (s, 1H), 10.27(s, 1H), 9.70 (s, 1H), 8.91 (d, J=2.1 Hz, 1H), 8.72 (d, J=0.9 Hz, 1H),8.60 (d, J=2.0 Hz, 1H), 8.18 (t, J=1.9 Hz, 2H), 7.90 (s, 1H), 7.66 (d,J=8.0 Hz, 1H), 7.58-7.55 (m, 1H), 7.52 (s, 1H), 7.48 (t, J=7.9 Hz, 1H),7.39 (s, 1H), 7.39-7.33 (m, 1H), 7.31 (d, J=7.9 Hz, 1H), 6.78 (d, J=15.4Hz, 1H), 6.59 (dd, J=3.4, 1.8 Hz, 1H), 6.30 (d, J=15.4 Hz, 1H), 3.10 (d,J=5.9 Hz, 2H), 2.21 (s, 6H).

Example 5. The Synthesis of THZ-CE-A-4-4

Tert-butyl3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate

Compound numbers 1 to 5 recited in Example 5 apply only to Example 5.5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo [2,3-b]pyridine(11 g, 30 mmol) and tert-butyl 3-aminopiperidine-1-carboxylate (7.2 g,36 mmol), DIEA (4.3 g, 33 mmol) was dissolved in 200 mL of NMP and washeated to 110° C. for overnight. The reaction mixture was poured intowater and ethyl acetate. The solid was filtrated, and the filtrate wasseparated, dried (Na₂SO₄), and concentrated. The residue was purified bya silica gel column to afford (8 g, 50%) of the title compound.

6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(piperidin-3-yl)pyrimidin-4-amine

Compound (1) (8 g, 15 mmol) was dissolved in dry DCM (80 mL) and was theadded TFA (40 mL) in an ice bath. The resulted mixture was stirred atroom temperature for overnight. Concentration to remove TFA to affordthe crude title compound which was used directly in the next step.

(4-nitrophenyl)(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidin-1-yl)methanone

Compound (2) (1.5 g, 3.45 mmol) in DCM (50 ml) was added TEA (0.42 g,4.14 mmol) and 4-nitrobenzoyl chloride (0.77 g, 4.14 mmol) at 0° C.After 3 hours stirring, it was diluted with DCM, washed with water andbrine, dried (Na₂SO₄), and concentrated. The residue was purified by asilica gel column to afford (1.2 g, 60%) of the title compound.

(4-aminophenyl)(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidin-1-yl)methanone

Compound (3) (1.2 g, 2 mmol) in methanol (40 mL) was added Pd/C (0.2 g),and the resulted mixture was stirred at room temperature for 12 hoursunder H₂. Then it was filtered through a short pad of CELITE andpurified by a silica gel column to afford (0.8 g, 73%) of the titlecompound.

(E)-4-(dimethylamino)-N-(4-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carbonyl)phenyl)but-2-enamide

Compound (4) (0.22 g, 0.4 mmol) and DIEA (0.08 g, 0.6 mmol) weredissolved in 10 mL of dry acetonitrile at 0° C. (E)-4-bromobut-2-enoylchloride (0.11 g, 0.6 mmol) in 5 mL of DCM was then added. After 5 minstirring, a solution of dimethylamine in THF (2N, 4 mL) was added, andthe solution was stirred for 1 hour. The reaction solution was dilutedwith DCM, washed with water and brine, dried (Na₂SO₄), and concentrated.The residue was purified by a silica gel column to afford (0.17 g, 64%)of the title compound.

(E)-N-(4-(3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide

Compound (5) (0.17 g, 0.25 mmol) in 10 mL of 1,4-dioxane was added 1Naqueous solution of sodium hydroxide. The solution was stirred at roomtemperature for 4 hours. Then the pH of the solution was adjusted to 7.0with 4M HCl. The solution was concentrated, and the residue was purifiedby a silica gel column to afford (68 mg, 52%) of the title compound MSm/z 525.26[M+H].

Example 6. The Synthesis of THZ-CE-A-4-5

Tert-butyl3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate

Compound numbers 1 to 5 recited in Example 6 apply only to Example 6. Ina sealed tube, 5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (11 g, 30 mmol) and tert-butyl3-aminopiperidine-1-carboxylate (7.2 g, 36 mmol), DIEA (4.3 g, 33 mmol)in 200 mL of NMP was heated to 110° C. for overnight. The reactionmixture was then cooled down and poured into water and ethyl acetate.The solution was filtrated and then was dried (Na₂SO₄) and concentrated.The residue was purified by a silica gel column to afford (8 g, 50%) ofthe title compound.

6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(piperidin-3-yl)pyrimidin-4-amine

Compound (1) (8 g, 15 mmol) was dissolved in dry DCM (80 mL) and was theadded TFA (40 mL) in an ice bath. The resulting mixture was stirred atroom temperature for overnight. Concentration to remove TFA to affordthe crude title compound which was used directly in the next step.

N-(3-nitrophenyl)-3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carboxamide

To a solution of Triphosgene (0.24 g, 0.8 mmol), TEA (0.71 g, 7 mmol) inDCM (30 mL) was added 3-nitroaniline (0.33 g, 2.4 mmol) in 10 mL of DCM.The mixture was stirred for 2 hours at 0° C. and a solution of compound(2) (0.87 g, 2 mmol) in DCM was added dropwise. Reaction solution wasallowed to stir overnight. After cooling down to room temperature, theproduct precipitated as solid (1 g, yield 83.3%).

N-(3-aminophenyl)-3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carboxamide

Compound (3) (1.29 g, 2.15 mmol), SnCl₂ (3.3 g, 17.24 mmol) in ethylacetate/methanol (4/1) (50 mL) was refluxed overnight. The solution wasthen cooled down to room temperature and then was diluted withchloroform/isopropyl alcohol (4/1). The solution was washed withsaturated sodium bicarbonate solution and then filtered by CELITE pad.The filtrate was dried over sodium sulfate and concentrated, and theproduct was obtained by flash chromatography withdichloromethane/methanol/ammonia (20/1/0.1-10/1/0.1) as eluent (0.9 g,yield 74%).

(E)-N-(3-(4-(dimethylamino)but-2-enamido)phenyl)-3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carboxamide

To solution of compound (4) (0.32 g, 0.56 mmol) and DIEA (0.11 g, 0.84mmol) in acetonitrile (18 mL) was add (E)-4-bromobut-2-enoyl chloride(0.154 g, 0.84 mmol) in DCM (9 mL). The reaction solution was stirredfor 5 min and then was added 2N solution of dimethylamine in THF (6 mL).After stirring for 1 hour, the solution was diluted with DCM, washedwith water and brine, dried (Na₂SO₄), and concentrated. The residue waspurified by a silica gel column to afford (0.26 g, 68%) of the titlecompound.

(E)-3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)-N-(3-(4-(dimethylamino)but-2-enamido)phenyl)piperidine-1-carboxamide

To a solution of compound (5) (0.26 g, 0.38 mmol) in 1,4-dioxane (15mL), 1M NaOH solution (15.0 mL) was added dropwise at 10° C., and thensolution was stirred at room temperature for 4 hours. The solution wasextracted with chloroform/2-propanol (4/1, vol/vol, 100 mL). The organiclayer was washed with water, brine, and dried over Na₂SO₄. The solventwas then removed, and the product was obtained by flash chromatographywith dichloromethane/methanol (20/1-10/1) as eluent (0.06 g, yield 30%).MS m/z 540.28[M+H]⁺.

Example 7. The Synthesis of THZ-CE-A-4-6

Tert-butyl4-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate

Compound numbers 1 to 5 recited in Example 7 apply only to Example 7. Ina sealed tube, 5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.925 g, 2.5 mmol) and tert-butyl4-aminopiperidine-1-carboxylate (1 g, 5 mmol), DIEA (0.48 g, 3.75 mmol)was dissolved in 20 mL of NMP, and the solution was heated to 130° C.for overnight. The solution was cooled down to room temperature and thenwas diluted with ethyl acetate (100 mL). The solution was washed withwater and brine. After drying with Na₂SO₄, the solvent was then removed,and the residue was purified by a silica gel column to afford (0.72 g,54%) of the title compound.

6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(piperidin-4-yl)pyrimidin-4-amine

To a solution of compound (1) (0.72 g, 1.34 mmol) in dry CH₂C₂(8 mL) wasadded TFA (4 mL) in an ice bath and the mixture was stirred at roomtemperature for 3 hours. TFA was then removed under a reduced pressure.The residue then was dissolved again in CH₂Cl₂ and then was washed withsaturated sodium bicarbonate solution. The solution was dried (Na₂SO₄)and concentrated to afford (0.52 g, 90%) of the title compound as crude.

(4-nitrophenyl)(4-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidin-1-yl)methanone

To a solution of compound (2) (0.72 g, 1.657 mmol) in CH₂Cl₂ (25 mL) wasadded TEA (0.2 g, 1.99 mmol) and 4-nitrobenzoyl chloride (0.37 g, 1.99mmol), and the solution was stirred at 0° C. for 4 hours. The reactionsolution was filtered to give a solid which was washed by petrol etherto give compound as crude (0.9 g, yield 93%).

(4-aminophenyl)(4-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidin-1-yl)methanone

The nitro compound (3) (0.9 g, 1.54 mmol), SnCl₂ (2.34 g, 12.34 mmol) inethyl acetate/methanol (4/1) (50 mL) was stirred and refluxed overnight.Reaction solution was then diluted with chloroform/isopropyl alcohol(4: 1) and then washed with saturated sodium bicarbonate solution. Thesolution was then filtered, dried with sodium sulfate, and concentrated.The product was obtained by flash chromatography withdichloromethane/methanol/ammonia (20/1/0.1-10/1/0.1) as eluent (0.7 g,yield 82%)

(E)-4-(dimethylamino)-N-(4-(4-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carbonyl)phenyl)but-2-enamide

To a solution of free amino compound (4) (0.4 g, 0.72 mmol) in driedacetonitrile (18 mL) was added DIEA (0.14 g, 1.08 mmol) and(E)-4-bromobut-2-enoyl chloride (0.2 g, 1.08 mmol) in dichloromethane (9mL) at 0° C. dropwise. After stirring for 5 min, the solution ofdimethylamine (2 M, 25 mL)) in THF was added, and the reaction mixturewas then stirred at the room temperature for 2 hours. The solution wasdiluted with water (100 mL), extracted with dichloromethane (3×100 mL).The resulted solution was washed with water and brine. After drying withNa₂SO₄, the solvent was then removed, and the product was obtained byflash chromatography with dichloromethane/methanol (20/1-10/1) as eluent(0.37 g, yield 77%).

(E)-N-(4-(4-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide(TH-P1-6)

To a solution of compound (5) (0.37 g, 0.51 mmol) in 1,4-dioxane (20mL), 1M NaOH solution (20 mL) was added dropwise at 10° C. and then wasstirred at room temperature for 6 hours. Extracted withchloroform/2-propanol (4/1, vol/vol, 100 mL). The organic layer waswashed with water, brine, and dried over Na₂SO₄, the solvent was thenremoved, and the product was obtained by flash chromatography withdichloromethane/methanol as eluent (0.09 g, yield 34%). MS m/z 525.26[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.23 (s, 1H), 8.86(s, 1H), 8.53 (d, J=17.4 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.56-7.51 (m,1H), 7.38 (d, J=8.6 Hz, 3H), 7.01 (s, 1H), 6.77 (dt, J=15.4, 5.9 Hz,1H), 6.56 (m, 1H), 6.29 (d, J=15.4 Hz, 1H), 3.40-2.18 (m, 5H), 3.07 (d,J=5.8 Hz, 2H), 2.19 (s, 6H), 1.97 (m, 2H), 1.46 (s, 2H).

Example 8. The Synthesis of THZ-CE-A-4-7

6-chloro-N-(3-nitrophenyl)pyrimidin-4-amine

Compound numbers 1 to 10 recited in Example 8 apply only to Example 8.To a solution of 3-nitroaniline (2.76 g, 20 mmol) and4,6-dichloropyrimidine (4.5 g, 30 mmol) was dissolved in NMP (30 mL),DIEA (3.9 g, 30 mmol) was added and then was heated at 130° C.overnight. The solution was cooled down to room temperature and then wasdiluted with ethyl acetate. The resulted solution was washed with brine.After drying with Na₂SO₄, the solvent was then removed, and the productwas obtained by flash chromatography with petroleum ether/ethyl acetate(5/1) as eluent (2.4g, yield 48%).

N¹-(6-chloropyrimidin-4-yl)benzene-1,3-diamine

6-chloro-N-(3-nitrophenyl)pyrimidin-4-amine (3) (2.4g, 9.6 mmol), SnCl₂(15g, 76.8 mmol) was dissolved in ethyl acetate/methanol (4/1) (125 mL)and was refluxed overnight. The solution was extracted by chloroform:isopropyl alcohol (4: 1) and washed with saturated sodium bicarbonatesolution. The pH was adjusted to about 8.0 and filtered through CELITEpad. The filtrate was dried over sodium sulfate. Concentrated to drynessto give the crude product (1.47g, yield 70%).

N¹-(6-(pyridin-4-yl)pyrimidin-4-yl)benzene-1,3-diamine

N¹-(6-chloropyrimidin-4-yl)benzene-1,3-diamine (1.47g, 6.7 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.75g, 13.4mmol), Na₂CO₃ (1.42g, 13.4 mmol) was dissolved in 40/20 mlacetonitrile/water and then was added Pd (dppf)₂Cl₂ CH₂Cl₂ (1 g). Thesolution was then degassed and was refluxed under nitrogen overnight.The solution was cooled down to room temperature, and the solid waswashed with petroleum ether. The solid was dissolved in dichloromethaneand then filtered. The filtrate was concentrated to dryness to give thecrude product (0.72g, yield 41%).

4-nitro-N-(3-((6-(pyridin-4-yl)pyrimidin-4-yl)amino)phenyl)benzamide

N1-(6-(pyridin-4-yl)pyrimidin-4-yl)benzene-1,3-diamine (6) (0.72g, 2.73mmol) was dissolved DCM (30 ml) and TEA (0.42g, 4.1 mmol) and4-nitrobenzoyl chloride (0.76g, 4.1 mmol) was then added. The reactionwas stirred at 0° C. for 3 hours. The solid was then washed withpetroleum ether to give the crude product (0.5g, yield 45%).

4-amino-N-(3-((6-(pyridin-4-yl)pyrimidin-4-yl)amino)phenyl)benzamide

To a solution of4-nitro-N-(3-((6-(pyridin-4-yl)pyrimidin-4-yl)amino)phenyl)benzamide (8)(0.72 g, 1.746 mmol) in ethyl acetate/methanol (4:1) (30 mL) was addedSnCl₂ (2.65 g, 13.97 mmol). The resulting mixture was heated at 80° C.for 8 hours. The pH of the solution was adjusted to 7 with 1 M NaOH. Itwas concentrated to afford (0.59 g, 88%) of the title compound (9) as asolid. MS m/z 382.15 [M+H]⁺.

(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(pyridin-4-yl)pyrimidin-4-yl)amino)phenyl)benzamide

4-amino-N-(3-((6-(pyridin-4-yl)pyrimidin-4-yl)amino)phenyl)benzamide(0.12g, 0.3 mmol), (E)-4-(dimethylamino)but-2-enoic acid (60 mg, 0.36mmol), and DIEA (60 mg, 0.45 mmol) were dissolved in DMF (2 mL), andHATU was added (0.171g, 0.45 mmol). The solution was stirred at roomtemperature for 1 hour. The solution was diluted with ethyl acetate andwater. The organic layer was washed twice with saturated sodiumbicarbonate, dried over sodium sulfate, concentrated, and the productwas obtained by flash chromatography with DCM/MeOH/NH₃=(8/1/0.1) aseluent (41 mg, yield 28%). MS m/z 494.23 [M+H]⁺.

Example 9. The Synthesis of THZ-CE-A-4-8

Tert-butyl3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate

Compound numbers 1 to 5 recited in Example 9 apply only to Example 9. Ina sealed tube, 5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (11 g, 30 mmol) and tert-butyl3-aminopiperidine-1-carboxylate (7.2 g, 36 mmol), DIEA (4.3 g, 33 mmol)in NMP (200 mL) were heated to 110° C. overnight. The reaction mixturewas cooled down and poured into water and ethyl acetate. The solutionwas filtrated and was washed with water, dried (Na₂SO₄), andconcentrated. The residue was purified by a silica gel column to afford(8 g, 50%) of the title compound.

6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(piperidin-3-yl)pyrimidin-4-amine

To a solution of compound (1) (8 g, 15 mmol) in dry CH₂Cl₂ (80 ml) wasadded dropwise TFA (40 mL). The resulted mixture was stirred at roomtemperature for overnight. The solution was then concentrated to removeTFA. The residue was dissolved again in CH₂Cl₂ (80 mL). The solution wasthen washed with saturated sodium bicarbonate solution, water, dried(Na₂SO₄), and concentrated to afford (5.5 g, 84.6%) of the titlecompound as crude.

N-(1-(4-nitrobenzyl)piperidin-3-yl)-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-amine

To Compound (2) (1.5 g, 3.45 mmol) in CH₂Cl₂(50 ml) was added TEA (0.42g, 4.14 mmol) and 1-(chloromethyl)-4-nitrobenzene (0.77 g, 4.14 mmol) at0° C., and then solution was stirred overnight. The solvent was thenremoved, and the residue was dissolved in CH₂Cl₂. Then product wasprecipitated by adding petroleum ether to the solution (1.7 g, yield87%).

N-(1-(4-aminobenzyl)piperidin-3-yl)-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-amine

Compound (3) (2.7 g, 4.7 mmol), and SnCl₂ (7.2 g, 38 mmol) weredissolved in ethyl acetate/methanol (4/1) (80 mL), and the solution wasstirred and refluxed overnight. The solution was extracted withchloroform/isopropyl alcohol (4: 1) and then washed with saturatedsodium bicarbonate solution, and water, dried (Na₂SO₄), andconcentrated. The product was obtained by flash chromatography withdichloromethane/methanol/ammonia (20/1/0.1-10/1/0.1) as eluent (2.0 g,yield 79%).

(E)-4-(dimethylamino)-N-(4-((3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidin-1-yl)methyl)phenyl)but-2-enamide

To Compound (4) (0.43 g, 0.8 mmol) and DIEA (0.16 g, 1.2 mmol) in dryacetonitrile (15 mL) was added (E)-4-bromobut-2-enoyl chloride (0.22 g,1.2 mmol) in CH₂Cl₂ (5 mL). After 5 min stirring, 2 N solution ofdimethylamine in THF (8 mL) was added and then was stirred for 1 hour.The reaction solution was extracted with CH₂Cl₂, washed with water andbrine, dried (Na₂SO₄), and concentrated. The residue was purified by asilica gel column to afford (0.13 g, 25%) of the title compound.

(E)-N-(4-(3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide

To Compound (5) (70 mg, 0.11 mmol) in 1,4-dioxane (5 mL) was added 1 Naqueous solution of sodium hydroxide (5 mL). The reaction was stirredfor 4 hours at room temperature. Then pH of the solution was adjusted to7.0 with 4 M HCl and diluted with CH₂C₂. The solution was dried (Na₂SO₄)and concentrated. The product was obtained by a prep TLC (DCM: MeOH=5:1)(15 mg, 26%). MS m/z 511.26[M+H]⁺.

Example 10. The Synthesis of THZ-CE-A-4-9

N1-(6-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-4-yl)benzene-1,3-diamine

Compound numbers 1 to 5 recited in Example 10 apply only to Example 10.5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(1) (10 g, 27 mmol) and benzene-1,3-diamine (4.73 g, 2.0 equiv) weredissolved in NMP (30 mL). DIEA (7 g, 54 mmol) was added, and then thesolution was heated at 150° C. overnight. The solution was cooled downto room temperature and then was diluted with ethyl acetate (100 mL).The resulted solution was washed with water and brine. After drying withNa₂SO₄, the solvent was then removed, and the product was obtained byflash chromatography with dichloromethane/methanol (30/1) as eluent (5.5g, yield 46%).

tert-butyl(3-((3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)carbamoyl)cyclohexyl)carbamate

To a dichloromethane solution of free amine compound (2) (1.5 g, 3.39mmol) was added 3-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylicacid (cis and trans, 0.9 g, 3.73 mmol) and HATU (1.55 g, 4.07 mol).After stirring for 3 hours at room temperature, the solution was dilutedwith water (100 mL), extracted with dichloromethane (3×50 mL). Theresulted solution was washed with water and brine. After drying withNa₂SO₄, the solvent was then removed, and the crude product was obtainedby flash chromatography with dichloromethane/methanol (50/1) as eluent(1.5 g, yield 60%).

3-amino-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)cyclohexane-1-carboxamide

To a methanol solution of compound (3) (1.5 g, 2.25 mmol) was addedhydrochloric ether, and the reaction solution was allowed to stir atroom temperature overnight. The solvent was then removed and ether wasadded. The filtering to give title compound as HCl salt (1.2 g, 90%).

(E)-3-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)cyclohexane-1-carboxamide

To a dichloromethane solution of free amine compound (4) (1.0 g, 1.76mmol) was added (E)-4-(dimethylamino)but-2-enoic acid hydrochloride(0.35 g, 2.11 mmol), DIEA (0.8g, 6.16 mmol) and HATU (0.8 g, 2.11 mol).After stirring for 12 hours at room temperature, the solution wasdiluted with water (100 mL), and extracted with dichloromethane (3×50mL). The resulted solution was washed with water and brine. After dryingwith Na₂SO₄, the solvent was then removed, and the product was obtainedby flash chromatography with dichloromethane/methanol (50/1-30/1) aseluent (0.5 g, 30%)

(E)-N-(3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)-3-(4-(dimethylamino)but-2-enamido)cyclohexane-1-carboxamide

To a solution of(E)-3-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)cyclohexane-1-carboxamide(5) (0.5 g, 0.7 mmol) in 1,4-dioxane (26.0 mL), 1M Sodium hydroxidesolution (26.0 mL) was added dropwise at 10° C. After stirring at roomtemperature for 6 hours, the solution was extracted withchloroform/2-propanol (4/1, vol/vol, 300 mL). The organic layer waswashed with water and brine, and dried over Na₂SO₄. The solvent was thenremoved, and the product was obtained by flash chromatography withdichloromethane/methanol (20/1-10/1) as eluent (0.15 g, 30%). MS m/z539.28 [M+H]⁺.

Example 11. The Synthesis of THZ-CE-A-4-10

tert-butyl(4-((3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)carbamoyl)cyclohexyl)carbamate

Compound numbers 1 to 4 recited in Example 11 apply only to Example 11.To a dichloromethane solution of free amine compound (1) (1.5 g, 3.39mmol) was added 4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylicacid (0.9 g, 3.73 mmol) and HATU (1.55 g, 4.07 mol). After stirring for3 hours at room temperature, the solution was diluted with water (100mL) and then was extracted with dichloromethane (3×50 mL). The resultedsolution was washed with water and brine. After drying with Na₂SO₄, thesolvent was then removed, and the crude product was obtained by flashchromatography with dichloromethane/methanol (50/1) as eluent (1.5 g,yield 60%).

4-amino-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)cyclohexane-1-carboxamide

To a methanol solution of compound (2) (1.5 g, 2.25 mmol) was addedhydrochloric ether, and the solution was stirred at room temperatureovernight. The solvent was then removed, and ether was then added. Theproduct was then obtained as HCl salt (1.2 g, yield 90%).

(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)cyclohexane-1-carboxamide

To a dichloromethane solution of free amine compound (3) (1.0 g, 1.76mmol) was added (E)-4-(dimethylamino)but-2-enoic acid hydrochloride(0.35 g, 2.11 mmol), DIEA (0.8 g, 6.16 mmol), and HATU (0.8 g, 2.11mmol). After stirring for 12 hours at room temperature, the solution wasdiluted with water (100 mL) and then extracted with dichloromethane(3×50 mL). The resulted solution was washed with water and brine. Afterdrying with Na₂SO₄, the solvent was then removed, and the crude productwas obtained by flash chromatography with dichloromethane/methanol(50/1-30/1) as eluent (0.5 g, yield 30%).

(E)-N-(3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)cyclohexane-1-carboxamide

To a solution of(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)cyclohexane-1-carboxamide(4) (0.5 g, 0.7 mmol) in 1,4-dioxane (26.0 mL), 1 M Sodium hydroxidesolution (26.0 mL) was added dropwise at 10° C. Then the solution wasstirred at room temperature for 6 hours and was extracted withchloroform/2-propanol (4/1, vol/vol, 300 mL). The organic layer waswashed with water and brine, and dried over Na₂O₄. The solvent was thenremoved, and the product was obtained by flash chromatography withdichloromethane/methanol (20/1-10/1) as eluent (0.15 g, yield 30%). MSm/z 539.28 [M+H]⁺.

Example 12. The Synthesis of THZ-CE-A-4-12

2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)aceticacid

Compound numbers 1 to 5 recited in Example 12 apply only to Example 12.To a solution of5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo-[2,3-b]pyridine(3.7 g, 10 mmol) in NMP (10 mL) was added 2-(3-aminophenyl)acetic acid(1.83 g, 12 mmol). The resulted mixture was heated at 140° C. for 12hours. Then it was diluted with EtOAc (200 mL) at room temperature,washed with water and brine, dried (Na₂SO₄), and concentrated. Theresidue was purified by a silica gel column to afford (0.3 g, 6.1%) ofthe title compound as a slightly yellow solid.

tert-butyl(1-(2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetyl)piperidin-4-yl)carbamate

To a solution of2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)aceticacid (0.3 g, 0.62 mmol) in DMF (2 mL) was added HATU (0.35 g, 0.93mmol), tert-butyl piperidin-4-ylcarbamate (0.19 g, 0.93 mmol), and DIEA(0.22 mL, 1.24 mmol). The resulting mixture was stirred at roomtemperature for 30 min. Then it was diluted with ethyl acetate (150 mL),washed with water and brine, dried (Na₂SO₄), and concentrated. Theresidue was purified by a silica gel column to afford (0.21 g, 51.2%) ofthe title compound as a white solid.

1-(4-aminopiperidin-1-yl)-2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)ethan-1-one

To a solution oftert-butyl(1-(2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetyl)piperidin-4-yl)carbamate(0.21 g, 0.31 mmol) in ethyl acetate (5 mL) was added 4 M HCl. Theresulted mixture was stirred at room temperature for 30 min. Then it wasdiluted with EtOAc (100 mL). The pH of the solution was adjusted to 7.0with 1 M NaOH. The organic layer was washed with water and brine, dried(Na₂SO₄), and concentrated to afford (0.15 g, 90.0%) of the titlecompound as a white solid.

(E)-4-(dimethylamino)-N-(1-(2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetyl)piperidin-4-yl)but-2-enamide

To a solution of1-(4-aminopiperidin-1-yl)-2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)ethan-1-one(0.5 g, 0.88 mmol) in DMF (2 mL) was added HATU (0.5 g, 1.32 mmol),(E)-4-(dimethylamino)but-2-enoic acid hydrochloride (0.18 g, 1.06 mmol),and DIEA (0.34 g, 2.7 mmol). The resulted mixture was stirred at roomtemperature for 30 min. Then it was diluted with DCM (200 mL), washedwith water and brine, dried (Na₂SO₄), and concentrated. The residue waspurified by a silica gel column to afford (0.3 g, 50%) of the titlecompound as a white solid.

(E)-N-(1-(2-(3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetyl)piperidin-4-yl)-4-(dimethylamino)but-2-enamide

(E)-4-(dimethylamino)-N-(1-(2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetyl)piperidin-4-yl)but-2-enamide(0.43 g, 0.6 mmol) was dissolved in a mixture of 1 M NaOH and1,4-dioxane (6 mL, 1/1, v/v). The resulted mixture was stirred at roomtemperature for 4 hours. Then the pH of the solution was adjusted to 7.0with 1 M HCl, and the resulted mixture was concentrated. The residue waspurified by a silica gel column to afford (180 mg, 56.2%) of the titlecompound as a white solid. MS m/z 539.28 [M+H]⁺. 1H NMR (400 MHz,DMSO-d6) δ 11.86 (s, 1H), 9.66 (s, 1H), 8.90 (d, J=2.1 Hz, 1H), 8.70 (s,1H), 8.59 (d, J=2.1 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.64 (d, J=9.2 Hz,1H), 7.57-7.49 (m, 2H), 7.32 (s, 1H), 7.29 (t, J=7.9 Hz, 1H), 6.92 (d,J=7.5 Hz, 1H), 6.58 (dd, J=3.2, 1.6 Hz, 1H), 6.56-6.49 (m, 1H), 6.01 (d,J=15.4 Hz, 1H), 4.26 (d, J=13.1 Hz, 1H), 3.92 (d, J=13.6 Hz, 1H), 3.84(d, J=7.2 Hz, 1H), 3.73 (s, 2H), 3.22-3.11 (m, 2H), 2.99 (d, J=5.9 Hz,2H), 2.82 (t, J=11.1 Hz, 1H), 2.15 (s, 6H), 1.74 (m, 2H).

Example 13. The Synthesis of THZ-CE-A-4-13

tert-butyl(4-(2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetamido)cyclohexyl)carbamate

Compound numbers 1 to 4 recited in Example 13 apply only to Example 13.To a solution of2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)aceticacid (0.3 g, 0.62 mmol) in DMF (2 mL) was added HATU (0.35 g, 0.93mmol), tert-butyl (4-aminocyclohexyl)carbamate (0.8 g, 3.75 mmol), andDIEA (0.65 g, 5 mmol). The resulting mixture was stirred at roomtemperature for 30 min. Then it was diluted with ethyl acetate (300 mL),washed with water and brine, dried (Na₂SO₄), and concentrated. Theresidue was purified by a silica gel column to afford (1.52 g, 89.2%) ofthe title compound as a white solid.

N-(4-aminocyclohexyl)-2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetamide

A solution oftert-butyl(4-(2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetamido)cyclohexyl)carbamate(1.52 g, 2.23 mmol) in 4 M HCl of EtOAc (20 mL) was stirred at roomtemperature for 30 min. Then it was diluted with EtOAc (300 mL). The pHof the solution was adjusted to 7.0 with 1 M NaOH. The organic layer waswashed with water and brine, dried (Na₂SO₄), and concentrated to afford(1.3g, 100%) of the title compound as a white solid.

(E)-4-(dimethylamino)-N-(1-(2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetyl)piperidin-4-yl)but-2-enamide

To a solution ofN-(4-aminocyclohexyl)-2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetamide(0.93 g, 1.5 mmol) in DMF (5 mL) was added HATU (0.9 g, 2.3 mmol),(E)-4-(dimethylamino)but-2-enoic acid hydrochloride (0.3 g, 1.8 mmol),and DIEA (0.58 g, 4.5 mmol). The resulting mixture was stirred at roomtemperature for 30 min. Then it was diluted with DCM (200 mL), washedwith water and brine, dried (Na₂SO₄), and concentrated. The residue waspurified by a silica gel column to afford (0.6 g, 58%) of the titlecompound as a white solid.

(E)-N-(4-(2-(3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetamido)cyclohexyl)-4-(dimethylamino)but-2-enamide

A solution of(E)-4-(dimethylamino)-N-(1-(2-(3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)acetyl)piperidin-4-yl)but-2-enamide(0.6 g, 0.87 mmol) in 1 M NaOH and 1,4-dioxane (10 mL, 1/1, v/v) wasstirred at room temperature for 4 hours. Then the pH of the solution wasadjusted to 7.0 with 1 M HCl, and the resulted mixture was concentrated.The residue was purified by a silica gel column to afford (230 mg, 48%)of the title compound as a white solid. MS m/z 553.30 [M+H]⁺.

Example 14. The Synthesis of THZ-CE-A-4-14

N-(2-methyl-5-nitrophenyl)-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-amine

Compound numbers 1 to 6 recited in Example 14 apply only to Example 14.To a solution of5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(1.5 g, 4 mmol) in 1,4-Dioxane was added 2-methyl-5-nitroaniline (1.23g, 8 mmol), Cs₂CO₃(1.4 g, 4.4 mmol), Pd₂(dba)₃(0.07 g, 0.08 mmol), and2-dicyclohexylphosphino-2′,4′,6′-triipropyl-1,1′-biphenyl(0.14 g, 0.24mmol). The resulted mixture was heated at 104° C. for 3 hours under N₂.Then it was diluted with EtOAc (1500 mL) at room temperature, washedwith water and brine, dried (Na₂SO₄), and concentrated. The residue waspurified by a silica gel column to afford (0.81 g, 42%) of the titlecompound as a slightly yellow solid.

6-methyl-N1-(6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)benzene-1,3-diamine

To a solution ofN-(2-methyl-5-nitrophenyl)-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-amine(4.2 g, 8.63 mmol) in MeOH (200 mL) was added SnCl₂(16.4 g, 86.3 mmol).The resulted mixture was heated at 80° C. for 8 hours. The pH of thesolution was then adjusted to 7.0 with 1 M NaOH. The solution wasconcentrated. The residue was purified by a silica gel column to afford(2.4 g, 61%) of the title compound as a slightly yellow solid.

tert-butyl(4-((4-methyl-3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)carbamoyl)phenyl)carbamate

To a solution of6-methyl-N1-(6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)benzene-1,3-diamine(0.91 g, 2.0 mmol) in DMF (5.0 mL) was added HATU (1.14 g, 3.0 mmol),4-((tert-butoxycarbonyl)amino)benzoic acid (0.71 g, 3.0 mmol), and DIEA(0.59 g, 4.0 mmol). The resulted mixture was stirred at room temperaturefor 30 min. Then it was diluted with ethyl acetate (300 mL), washed withwater and brine, dried (Na₂SO₄), and concentrated. The residue waspurified by a silica gel column to afford (1 g, 74%) of the titlecompound as a slightly yellow solid.

4-amino-N-(4-methyl-3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide

A solution oftert-butyl(4-((4-methyl-3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)carbamoyl)phenyl)carbamate(1 g, 1.5 mmol) in 4 M HCl of EtOAc (5.0 mL) was stirred at roomtemperature for 30 min. Then it was diluted with EtOAc (100 mL). The pHof the solution was adjusted to 7 with 1 M NaOH. The organic layer waswashed with water and brine, dried (Na₂SO₄), and concentrated to afford(0.8 g, 85%) of the title compound as a white solid.

(E)-4-(4-(dimethylamino)but-2-enamido)-N-(4-methyl-3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide

To a solution of4-amino-N-(4-methyl-3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(0.4 g, 0.7 mmol) in DCM (10 mL) was added DIEA (0.27 g, 2.1 mmol) and(E)-4-bromobut-2-enoyl chloride (0.23 g, 1.25 mmol) at 0° C. for 30 min.Then it was added 2.0 M dimethylamine in THF (3.5 mL). The resultedmixture was stirred at room temperature for 2 hours. Then it wasconcentrated and purified by a silica gel column to afford (0.2 g, 42%)of the title compound as a slightly yellow solid.

(E)-N-(3-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)-4-methylphenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide

A solution of(E)-4-(4-(dimethylamino)but-2-enamido)-N-(4-methyl-3-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(0.2 g, 0.3 mmol) in 1 M NaOH and 1,4-dioxane (6 mL, 1/1, v/v) wasstirred at room temperature for 4 hours. Then the pH of the solution wasadjusted to 7.0 with 1M HCl, and the resulted mixture was concentrated.The residue was purified by a silica gel column to afford (26 mg, 16%)of the title compound as a white solid. MS m/z 547.25 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.45 (s, 1H), 10.18 (s, 1H), 9.08(s, 1H), 8.90 (s, 1H), 8.60 (d, J=6.5 Hz, 2H), 7.97 (s, 3H), 7.81 (d,J=7.8 Hz, 2H), 7.56 (s, 2H), 7.27 (d, J=7.7 Hz, 1H), 7.21 (s, 1H), 6.79(d, J=15.0 Hz, 1H), 6.57 (s, 1H), 6.36 (d, J=15.0 Hz, 1H), 3.22 (s, 2H),2.28 (s, 6H), 2.24 (s, 3H).

Example 15. The Synthesis of THZ-CE-A-4-15

tert-butyl(4-chloro-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)carbamate

Compound numbers 1 to 7 recited in Example 15 apply only to Example 15.To a stirred suspension of1-(phenylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(6.0 g, 15 mmol) in acetonitrile and water (50 mL) was added tert-butyl(4,6-dichloropyrimidin-2-yl)carbamate (5 g, 19 mmol), NaHCO₃(2g, 29.74mmol), and Bis(triphenylphosphine)palladium(II) chloride (0.2 g), andthe solution was refluxed overnight under N₂. Ethyl acetate and waterwere added, and the reaction mixture was filtered over CELITE. Theorganic layer was dried by Na₂SO₄, the solvent was then removed, and theproduct was obtained by flash chromatography with Hexane/Ethylacetate=(10/1) as eluent (3 g, yield 30%).

tert-butyl(4-((3-aminophenyl)amino)-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)carbamate

Tert-butyl(4-chloro-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)carbamate(2) (1.5 g, 3.1 mmol), benzene-1,3-diamine (0.38 g, 2.0 equiv), Cesiumcarbonate (1.5g, 0.06 eq), and Pd₂(dba)₃(0.06 g, 0.05 eq) were dissolvedin 1,4-dioxane (30 mL) and then were refluxed overnight under nitrogen.The solution was cooled down to room temperature and then was dilutedwith 300 mL of ethyl acetate. The resulted solution was washed withwater and brine. After drying with Na₂SO₄, the solvent was then removed,and the product was obtained by flash chromatography withdichloromethane/methanol (100/1) as eluent (1 g, yield 50%).

tert-butyl(4-((3-(4-nitrobenzamido)phenyl)amino)-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)carbamate

To a dichloromethane solution of free amine compound (3) (1.6 g, 2.9mmol) was added 4-nitrobenzoyl chloride (0.64 g, 1.2 equiv), andtriethylamine (0.5 g). After stirring for 3 hours at room temperature,the solution was diluted with of water (100 mL), and extracted withethyl acetate (3×100 mL). The resulted solution was washed with waterand brine. After drying with Na₂SO₄, the solvent was then removed, andthe crude product was obtained by flash chromatography withdichloromethane/methanol (50/1) as eluent (1.5 g, yield 70%).

tert-butyl(4-((3-(4-aminobenzamido)phenyl)amino)-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)carbamate

The nitro compound (4) (2.4 g, 3.38 mmol) was dissolve in ethylacetate/methanol (10:1, vol/vol, 70 mL), and the resulted suspension wastreated with Pd/C (0.5 g). After nitrogen replacement three times, thereaction mixture was stirred at the room temperature overnight. Thereaction mixture was filtered over CELITE, the solvent was then removed,and the product was obtained by flash chromatography with petroleumether/ethyl acetate/NH₃=(3/1/0.1) as eluent (2.2 g, yield 90%).

tert-butyl(E)-(4-((3-(4-(4-(dimethylamino)but-2-enamido)benzamido)phenyl)amino)-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)carbamate

To a dichloromethane solution of free amine compound (5) (1.0 g, 1.5mmol) was added (E)-4-(dimethylamino)but-2-enoic acid (0.35 g, 2.11mmol), DIEA (0.8g, 6.16 mmol) and HATU (0.8 g, 2.11 mol). After stirringfor 12 hours at room temperature, the solution was diluted with water,and extracted with dichloromethane (3×50 mL). The resulted solution waswashed with water and brine. After drying with Na₂SO₄, the solvent wasthen removed, and the crude product was obtained by flash chromatographywith dichloromethane/methanol (50/1-30/1) as eluent (0.2 g, yield 20%).

(E)-N-(3-((2-amino-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide

To a solution of tert-butyl(E)-(4-((3-(4-(4-(dimethylamino)but-2-enamido)benzamido)phenyl)amino)-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-2-yl)carbamate(6) (0.2 g) in methanol (26.0 mL), 1M HCl of diethyl ether solution(26.0 mL) was added dropwise at 10° C. The solution was then stirred atroom temperature for 12 hours. The solvent was then removed, and theproduct was obtained by flash chromatography withdichloromethane/methanol (50/1-10/1) as eluent (0.18 g, yield 95%).

(E)-N-(3-((2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide

A solution of(E)-N-(3-((2-amino-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide(7) (0.18 g, 0.26 mmol) in 1,4-dioxane (6.0 mL) and 1M NaOH solution(6.0 mL) was stirred at room temperature for 12 hours. The solution wasthen extracted with chloroform/2-propanol (4/1, vol/vol, 300 mL). Theorganic layer was washed with water and brine, and dried over Na₂SO₄.The solvent was then removed, and the product was obtained by flashchromatography with dichloromethane/methanol (20/1-10/1) as eluent (30mg, yield 23%). MS m/z 547.24 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 11.78(s, 1H), 10.49 (s, 1H), 10.09 (s, 1H), 9.26 (s, 1H), 8.82 (d, J=2.1 Hz,1H), 8.49 (d, J=1.5 Hz, 1H), 8.12 (d, J=18.7 Hz, 1H), 7.97 (d, J=8.7 Hz,2H), 7.82 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.7 Hz, 1H), 7.55-7.44 (m, 1H),7.37 (d, J=8.6 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 6.80 (m, 2H), 6.66 (s,1H), 6.56 (m, 1H), 6.44-6.21 (m, 2H), 3.30-3.14 (m, 2H), 2.27 (s, 6H).

Example 16. The Synthesis of THZ-CE-A-4-19

1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

Compound numbers 1 to 11 recited in Example 16 apply only to Example 16.To a stirred suspension of 6-bromo-1-methyl-1H-indazole (1.0 g, 4.7mmol) in 1,4-Dioxane (20 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.43 g,5.64 mmol), potassium acetate (0.69 g, 7.0 mmol), and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.17 g,0.23 mmol), and the solution was then refluxed overnight under nitrogen.The solvent was then removed, and the product was obtained by flashchromatography with petroleum ether/ethyl acetate=(10/1) as eluent (1.2g, yield 70%).

6-(6-chloropyrimidin-4-yl)-1-methyl-1H-indazole

To a stirred suspension of1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(1.2 g, 4.7 mmol) in acetonitrile (20 mL) and water (5 mL) was added4,6-dichloropyrimidine (0.7 g, 4.65 mmol), sodium bicarbonate (0.69 g,7.05 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.016g, 0.0235 mmol), and then the solution was refluxed overnight undernitrogen. The solvent was then removed, and the product was obtained byflash chromatography with petroleum ether/ethyl acetate=(3/1) as eluent(0.8 g, yield 70%).

N1-(6-(1-methyl-1H-indazol-6-yl)pyrimidin-4-yl)benzene-1,3-diamine

6-(6-chloropyrimidin-4-yl)-1-methyl-1H-indazole (5) (0.8 g, 3.27 mmol)and benzene-1,3-diamine (0.7 g, 4.9 mmol) were dissolved in NMP (30 mL)and then were heated at 150° C. overnight. The solution was cooled downto room temperature and then was diluted with ethyl acetate. Theresulted solution was washed with water and brine. After drying withNa₂SO₄, the solvent was then removed, and the product was obtained (0.5g, yield 50%).

N-(3-((6-(1-methyl-1H-indazol-6-yl)pyrimidin-4-yl)amino)phenyl)-4-nitrobenzamide

To a dichloromethane solution of free amine compound (7) (0.5 g, 1.58mmol) and TEA (0.2 g, 1.89 mmol) was added 4-nitrobenzoyl chloride (0.45g, 2.3 mmol). After stirring for 5 hours at room temperature, thesolution was filtered, and the crude product was washed withdichloromethane (0.6 g, yield 99%).

4-amino-N-(3-((6-(1-methyl-1H-indazol-6-yl)pyrimidin-4-yl)amino)phenyl)benzamide

The nitro compound (9) (0.6 g) was dissolve in ethyl acetate/methanol(10:1, vol/vol, 20 mL), and the resulted suspension was treated withPd/C (0.3 g). After nitrogen replacement three times, the reactionmixture was stirred at the room temperature overnight. The reactionmixture was filtered over CELITE, the solvent was then removed, and theproduct was obtained by flash chromatography with petroleumdichloromethane/methanol (20/1) as eluent (0.6 g, yield 100%).

(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((6-(1-methyl-1H-indazol-6-yl)pyrimidin-4-yl)amino)phenyl)benzamide

To a dichloromethane solution of free amine compound (10) (0.6 g, 1.76mmol) was added (E)-4-(dimethylamino)but-2-enoic acid (0.35 g, 2.11mmol), DIEA (0.21 g, 6.16 mmol), and HATU (0.6 g, 2.11 mol). Afterstirring for 12 hours at room temperature, the solution was diluted withwater (100 mL), and extracted with dichloromethane (3×50 mL). Theresulted solution was washed with water and brine. After drying withNa₂SO₄, the solvent was then removed, and the crude product was obtainedby flash chromatography with dichloromethane/methanol (15/1) as eluent(0.2g, yield 30%). MS m/z 547.25 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ10.33 (s, 1H), 10.17 (s, 1H), 9.66 (s, 1H), 8.70 (d, J=1.0 Hz, 1H), 8.51(s, 2H), 8.17 (t, J=2.0 Hz, 1H), 8.03-7.94 (m, 2H), 7.90 (dd, J=9.1, 1.7Hz, 1H), 7.83-7.76 (m, 2H), 7.71 (dd, J=5.4, 4.6 Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 7.40 (dd, J=7.1, 1.9 Hz, 1H), 7.35-7.24 (m, 2H), 6.79 (dt,J=15.4, 5.8 Hz, 1H), 6.31 (dt, J=15.4, 1.6 Hz, 1H), 4.20 (s, 3H), 3.08(dd, J=5.9, 1.4 Hz, 2H), 2.19 (s, 6H).

Example 17. The Synthesis of THZ-CE-A-4-17

4-chloro-6-((6-methoxypyridin-3-yl)oxy)pyrimidine

Compound numbers 1 to 9 recited in Example 17 apply only to Example 17.To a stirred suspension of 6-methoxypyridin-3-ol (1.0 g, 8 mmol) inacetonitrile (50 mL) was added 4,6-dichloropyrimidine (1.4 g, 9.6 mmol),sodium bicarbonate (0.8 g, 9.6 mmol), and the solution was refluxedovernight under nitrogen. The solvent was then removed, and the productwas obtained by flash chromatography with petroleum ether/ethylacetate=(20/1) as eluent (1.85 g, yield 80%).

N1-(6-((6-methoxypyridin-3-yl)oxy)pyrimidin-4-yl)benzene-1,3-diamine

4-chloro-6-((6-methoxypyridin-3-yl)oxy)pyrimidine (3) (1.85 g, 7.8 mmol)and benzene-1,3-diamine (1 g, 9.37 mmol) were dissolved in NMP (30 mL)and then were heated at 150° C. overnight. The solution was cooled downto room temperature and then was diluted with ethyl acetate (300 mL).The resulted solution was washed with water and brine. After drying withNa₂SO₄, the solvent was then removed, and the product was obtained byflash chromatography with dichloromethane/methanol (100/1-50/1) aseluent (1.75 g, yield 65%).

N-(3-((6-((6-methoxypyridin-3-yl)oxy)pyrimidin-4-yl)amino)phenyl)-4-nitrobenzamide

To a dichloromethane solution of free amine compound (5) (1.75 g, 5.66mmol) and TEA (1.23 g, 5.66 mmol) was added 4-nitrobenzoyl chloride (1g, 5.66 mmol). After stirring for 5 hours at room temperature, thesolution was filtered, and the crude product was wash withdichloromethane (0.89 g, yield 33%).

4-amino-N-(3-((6-((6-methoxypyridin-3-yl)oxy)pyrimidin-4-yl)amino)phenyl)benzamide

The nitro compound (7) (0.89 g, 3.38 mmol) was dissolve in ethylacetate/methanol (0:1, vol/vol, 70 mL), and the resulted suspension wastreated with Pd/C (0.3 g). After nitrogen replacement three times, thereaction mixture was stirred at the room temperature overnight. Thereaction mixture was filtered over CELITE, the solvent was then removed,and the product was obtained (0.85 g, yield 100%).

(E)-4-(4-(dimethylamino)but-2-enamido)-N-(3-((6-((6-methoxypyridin-3-yl)oxy)pyrimidin-4-yl)amino)phenyl)benzamide

To a solution of free amino compound (8) (0.4 g, 1.0 mmol) in driedacetonitrile (20 mL) was added N,N-Diisopropylethylamine (0.4 g, 3.0mmol) and (E)-4-bromobut-2-enoyl chloride (0.25 g, 1.5 mmol) indichloromethane (15 mL) at 0° C. dropwise. After stirring for 5 min, thesolution of dimethylamine (2 M, 10 mL)) in THF was added, and thereaction mixture was then stirred at the room temperature for 2 hours.The solution was diluted with water and extracted with dichloromethane(3×100 mL). The resulted solution was washed with water and brine. Afterdrying with Na₂SO₄, the solvent was then removed, and the product wasobtained by flash chromatography with dichloromethane/methanol (20/1) aseluent (90 mg, yield 15%). MS m/z 540.23 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d6) δ 10.32 (s, 1H), 10.14 (s, 1H), 9.64 (s, 1H), 8.33 (d, J=0.8Hz, 1H), 8.11-8.00 (m, 2H), 7.99-7.88 (m, 2H), 7.84-7.73 (m, 2H), 7.64(dd, J=8.9, 2.9 Hz, 1H), 7.39 (dd, J=6.1, 4.1 Hz, 2H), 7.28 (t, J=8.1Hz, 1H), 6.90 (d, J=8.9, 1H), 6.79 (dt, J=15.4, 5.8 Hz, 1H), 6.38-6.15(m, 2H), 3.87 (s, 3H), 3.08 (d, J=5.8 Hz, 2H), 2.19 (s, 6H).

Example 18. The Synthesis of THZ-CE-A-4-18

3-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole

Compound numbers 1 to 5 recited in Example 18 apply only to Example 18.To a solution of5-(6-chloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine(5) (1.85 g, 5 mmol) and benzene-1,4-diamine (0.81 g, 1.5 equiv) in NMP,DIEA (0.97 g, 7.5 mmol) was added, and then the solution was heated at150° C. overnight. The solution was cooled down to room temperature andthen was diluted with ethyl acetate. The resulted solution was washedwith water and brine. After drying with Na₂SO₄, the solvent was thenremoved, and the product was obtained by flash chromatography withdichloromethane/methanol (100/1) as eluent (1.3 g, yield 60%).

4-nitro-N-(4-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide

To a dichloromethane solution of free amine compound (2) (0.6 g, 1.36mmol) and TEA (0.2 g, 1.63 mmol) was added 4-nitrobenzoyl chloride (0.3g, 1.2 equiv). After stirring for 1.5 hours at room temperature. Thesolution was filtered, the crude product was wash with dichloromethane(0.65 g, yield 85%).

4-amino-N-(4-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide

The nitro compound (3) (0.65 g, 1.1 mmol) was dissolved in ethylacetate/methanol (0:1, vol/vol, 70 mL) and the resulted suspension wastreated with Pd/C (0.15 g). After nitrogen replacement three times, thereaction mixture was stirred at the room temperature overnight. Thereaction mixture was filtered over CELITE, the solvent was then removed,and the product was obtained by flash chromatography with petroleumether/ethyl acetate/NH₃=(3/1/0.1) as eluent (0.4 g, yield 60%).

(E)-4-(4-(dimethylamino)but-2-enamido)-N-(4-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide

To a solution of free amino compound (10) (0.4 g, 0.7 mmol) in driedacetonitrile (60 mL) was added N,N-Diisopropylethylamine (0.11 g, 0.84mmol) and (E)-4-bromobut-2-enoyl chloride (0.15 g, 0.84 mmol) indichloromethane (15 mL) at 0° C. dropwise. After stirring for 5 min, thesolution of dimethylamine (2 M, 7 mL) in THF was added, and the reactionmixture was then stirred at the room temperature for 2 hours. Thesolution was diluted with water and extracted with dichloromethane(3×100 mL). The resulted solution was washed with water and brine. Afterdrying with Na₂SO₄, the solvent was then removed, and the product wasobtained by flash chromatography with dichloromethane/methanol (50/1) aseluent (0.17 g, yield 30%).

(E)-N-(4-((6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide

A solution of(E)-4-(4-(dimethylamino)but-2-enamido)-N-(4-((6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)amino)phenyl)benzamide(0.17 g) in 1,4-dioxane (26.0 mL) and a 1 M NaOH solution (5.0 mL) wasstirred at room temperature for 6 hours. The solution was extracted withchloroform/2-propanol (4/1, vol/vol, 300 mL). The organic layer waswashed with water and brine and dried over Na₂SO₄. The solvent was thenremoved, and the product was obtained by flash chromatography withdichloromethane/methanol (15/1-10/1) as eluent (22 mg, yield 10%). MSm/z 533.23 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.34 (s,1H), 10.11 (s, 1H), 9.61 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.57 (s,1H), 7.96 (d, J=8.7 Hz, 2H), 7.90-7.77 (m, 4H), 7.67 (d, J=9.1 Hz, 2H),7.59-7.51 (m, 1H), 7.26 (s 1H), 6.79 (m, 1H), 6.59 (m, 1H), 6.32 (d,J=15.2 Hz, 1H), 3.13 (s, 2H), 2.28 (s, 6H).

Biological Evaluation Example 19. Kinase Assay

PIP4K in vitro kinase assay was carried out as described in Rameh et al(Nature, 1997). Briefly, 0.1 ug (μg) of GST-PI5P4Ka or 0.4 ug ofGST-PI5P4Ka resuspended in 70 uL (μL) of kinase buffer containing 20 mMHEPES pH 7.4, 100 mM NaCl, 0.5 mM EGTA was stabilized at roomtemperature for 10 minutes and incubated with 1 uM of DMSO or indicatedcompound for 30 minutes. Then the kinase reaction was carried out in atotal volume of 100 ul (μL) for 10 minutes by adding 20 uL of lipidsubstrates (4 ug of phosphatidylserine and 2 ug of PI5P) in buffercontaining 30 mM HEPES pH 7.4 and 1 mM EGTA, and 10 uL of ATP mix (500uM (μM) non-radiolabeled ATP, 10 uCi [g-³²P]-ATP, 65 mM HEPES pH 7.4 and100 mM MgCl₂). The reaction was terminated by adding 50 uL of HCl.Phosphoinositides were extracted by adding 100 uL methanol/chloroform(1:1, vol:vol) mix and subjected to thin layer chromatography separationusing heat-activated 1% potassium oxalate-coated silica gel 60 plates(EMD Chemicals Inc., Billerica, Mass., USA) and a 1-propanol/2 M aceticacid (65:35, vol:vol) solvent system. The radiolabeled PI(4,5)P₂ wasquantified with a Phosphorimager (Molecular Dynamics, STORM840, GEHealthcare, Waukesha, Wis., USA).

Example 20. Cell Proliferation Assay

To determine cell proliferation, cells were plated at 2×10³ cells perwell of 96-well plate. Cells were incubated and assayed at indicatedtimes using Cell TITER-GLO Luminescent Cell Viability assay (Promega).Cells were allowed to equilibrate to room temperature for 15 minutes,then an equal volume of the Cell TITER-GLO reagent was added to wellsand incubated for 15 minutes on an orbital shaker. Luminescence wasrecorded according to the manufacturer's protocol.

Example 21. ADP-GLO Assay on PIP4K2A

PIP5K2A enzyme (diluted in 12.5 mM Glycine-NaOH (pH 8.5), 50 mM KCl, 2.5mM MgCl₂, 1 mM DTT, 0.25% Na-Cholate, and 1 mg/ml BSA) was assayed intotal volume of 20 μl containing 12.5 mM Glycine-NaOH (pH 8.5), 50 mMKCl, 2.5 mM MgCl₂, 1 mM DTT, 0.25% Na-Cholate, 0.01 mM ATP, and 0.05 mMdiC8 PI(5)P. The enzyme was assayed for 15 min after which 20 μl ofADP-GLO reagent was added. After a further incubation of 40 minutes, 40μl of Kinase Detection Buffer was added. After a further incubation of40 min, the enzyme was read on PERKINELMER ENVISION for 1 sec/well.Exemplary results are shown in Table 1.

TABLE 1 Exemplary IC₅₀ values of select compounds on PIP4K2A CompoundNumber THZ-CE-A-4-2 THZ-CE-A-4-3 THZ-CE-A-4-9 THZ-CE-A-4-18 THZ-CE-A-4IC₅₀ (μM) 0.06 0.01 0.25 0.05 0.33

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ring A is asubstituted or unsubstituted heteroaryl ring; each instance of R^(A) isindependently halogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, —OR^(a), —N(R^(a))₂, —SR^(a), —CN, —SCN,—C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), —C(═NR^(a))N(R^(a))₂, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂, —NR^(a)C(═O)R^(a),—NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂, —OC(═O)R^(a), —OC(═O)OR^(a),or —OC(═O)N(R^(a))₂; each instance of R^(a) is independently hydrogen,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a nitrogen protecting groupwhen attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two instances of R^(a) are joined to form asubstituted or unsubstituted, heterocyclic ring, or substituted orunsubstituted, heteroaryl ring; k is 0, 1, 2, 3, 4, 5, or 6; L¹ is abond, —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR^(c)—;each instance of R^(b) is independently hydrogen, halogen, orsubstituted or unsubstituted C₁₋₆ alkyl; each instance of R^(c) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group; R^(B1) is hydrogen, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂; R^(B2) is hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(a), —N(R^(a))₂, —SR^(a), —CN, —SCN, —C(═NR^(a))R^(a),—C(═NR^(a))OR^(a), —C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)N(R^(a))₂, —NO₂, —NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a),—NR^(a)C(═O)N(R^(a))₂, —OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;X is —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR^(c)—,—C(R^(b))₂C(R^(b))₂—, —C(R^(b))₂C(═O)—, —C(═O)C(R^(b))₂—,(E)-CR^(b)═CR^(b)—, (Z)—CR^(b)═CR^(b)—, —C≡C—, —OC(═O)—, —C(═O)O—,—SC(═O)—, —C(═O)S—, —NR^(c)C(═O)—, —C(═O)NR^(c)—, —OC(R^(b))₂—,—C(R^(b))₂O—, —SC(R^(b))₂—, —C(R^(b))₂S—, —NR^(c)C(R^(b))₂—,—C(R^(b))₂NR^(c)—, —S(═O)O—, —OS(═O)—, —S(═O)NR^(c)—, —NR^(c)S(═O)—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(c)—, or —NR^(c)S(═O)₂—; Ring C is asubstituted or unsubstituted phenyl ring, substituted or unsubstituted,monocyclic carbocyclic ring, substituted or unsubstituted, monocyclicheterocyclic ring, or substituted or unsubstituted, monocyclicheteroaryl ring; Ring D is a substituted or unsubstituted phenyl ring,substituted or unsubstituted, monocyclic carbocyclic ring, orsubstituted or unsubstituted, monocyclic heterocyclic ring; providedthat at least one of Ring C and Ring D is a substituted or unsubstitutedphenyl ring; each instance of R^(C) is independently halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(a), —N(R^(a))₂, —SR^(a), —CN, —SCN, —C(═NR^(a))R^(a),—C(═NR^(a))OR^(a), —C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)N(R^(a))₂, —NO₂, —NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a),—NR^(a)C(═O)N(R^(a))₂, —OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; L² is —C(R^(b))₂—, —C(═O)—,—O—, —S—, —S(═O)—, —S(═O)₂—, —NR^(c)—, —C(R^(b))₂C(R^(b))₂—,—C(R^(b))₂C(═O)—, —C(═O)C(R^(b))₂—, (E)-CR^(b)═CR^(b)—,(Z)—CR^(b)═CR^(b)—, —C≡C—, —OC(═O)—, —C(═O)O—, —SC(═O)—, —C(═O)S—,—NR^(c)C(═O)—, —C(═O)NR^(c)—, —OC(R^(b))₂—, —C(R^(b))₂O—, —SC(R^(b))₂—,—C(R^(b))₂S—, —NR^(c)C(R^(b))₂—, —C(R^(b))₂NR^(c)—, —S(═O)O—, —OS(═O)—,—S(═O)NR^(c)—, —NR^(c)S(═O)—, —S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(c)—,—NR^(c)S(═O)₂—, —OC(═O)O—, —NR^(c)C(═O)O—, —OC(═O)NR^(c)—,—NR^(c)C(═O)NR^(c)—, —C(R^(b))₂C(═O)C(R^(b))₂—, —OC(═O)C(R^(b))₂—,—C(R^(b))₂C(═O)O—, —NR^(c)C(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)NR^(c)—, or asubstituted or unsubstituted C₁₋₄ hydrocarbon chain, optionally whereinone or more carbon units of the hydrocarbon chain are independentlyreplaced with —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR^(c)—; eachinstance of R^(D) is independently halogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂; p is 0, 1, 2, 3, 4, 5,6, 7, 8, or 9; R^(E) is of the formula:

L³ is —C(R^(b))₂—, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NR^(c)—,—C(R^(b))₂C(R^(b))₂—, —C(R^(b))₂C(═O)—, —C(═O)C(R^(b))₂—,(E)-CR^(b)═CR^(b)—, (Z)—CR^(b)═CR^(b)—, —C≡C—, —OC(═O)—, —C(═O)O—,—SC(═O)—, —C(═O)S—, —NR^(c)C(═O)—, —C(═O)NR^(c)—, —OC(R^(b))₂—,—C(R^(b))₂O—, —SC(R^(b))₂—, —C(R^(b))₂S—, —NR^(c)C(R^(b))₂—,—C(R^(b))₂NR^(c)—, —S(═O)O—, —OS(═O)—, —S(═O)NR^(c)—, —NR^(c)S(═O)—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(c)—, —NR^(c)S(═O)₂—, —OC(═O)O—,—NR^(c)C(═O)O—, —OC(═O)NR^(c)—, —NR^(c)C(═O)NR^(c)—,—C(R^(b))₂C(═O)C(R^(b))₂—, —OC(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)O—,—NR^(c)C(═O)C(R^(b))₂—, —C(R^(b))₂C(═O)NR^(c)—, or a substituted orunsubstituted C₁₋₄ hydrocarbon chain, optionally wherein one or morecarbon units of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR^(c)—; L⁴ is a bond orsubstituted or unsubstituted C₁₋₆ hydrocarbon chain; each of R^(E1),R^(E2), and R^(E3) is independently hydrogen, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —CN, —CH₂R^(a),—CH₂N(R^(a))₂, —CH₂SR^(a), —OR, —N(R^(a))₂, —SR, or —Si(R^(a))₃; orR^(E1) and R^(E3), or R^(E2) and R^(E3), or R^(E1) and R^(E2) are joinedto form a substituted or unsubstituted, carbocyclic ring, or substitutedor unsubstituted, heterocyclic ring; R^(E4) is a leaving group; R^(E5)is halogen; R^(E6) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl,or a nitrogen protecting group; each instance of Y is independently O,S, or NR^(c); a is 1 or 2; and each instance of z is independently 0, 1,2, 3, 4, 5, or
 6. 2. The compound of claim 1, wherein Ring C is asubstituted or unsubstituted phenyl ring, substituted or unsubstituted,monocyclic carbocyclic ring, or substituted or unsubstituted, monocyclicheterocyclic ring.
 3. The compound of claim 1 or 2, wherein the compoundis of Formula (II):

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1 or 2, wherein the compound is of Formula (II-a):

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1 or 2, wherein the compound is of Formula (II-b):

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1 or 2, wherein the compound is of Formula (III):

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1 or 2, wherein the compound is of Formula (III-a):

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1 or 2, wherein the compound is of Formula (III-b):

or a pharmaceutically acceptable salt thereof.
 11. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1 or 2, wherein the compound is of Formula (IV):

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1 or 2, wherein the compound is of Formula (IV-a):

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim1 or 2, wherein the compound is of Formula (V):

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim1 or 2, wherein the compound is of Formula (V-a):

or a pharmaceutically acceptable salt thereof.
 19. The compound of claim1 or 2, wherein the compound is of Formula (V-b):

or a pharmaceutically acceptable salt thereof.
 20. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 21. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 22. The compound of claim1 or 2, wherein the compound is of Formula (VI):

or a pharmaceutically acceptable salt thereof.
 23. The compound of claim1 or 2, wherein the compound is of Formula (VI-a):

or a pharmaceutically acceptable salt thereof.
 24. The compound of claim1 or 2, wherein the compound is of the formula

or a pharmaceutically acceptable salt thereof.
 25. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 26. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 27. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 28. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 29. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 30. The compound of claim1 or 2, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 31. The compound of anyone of claims 1-30, wherein Ring A is a substituted or unsubstituted,bicyclic heteroaryl ring.
 32. The compound of claim 31, wherein Ring Ais a substituted or unsubstituted, 9- or 10-membered, bicyclicheteroaryl ring, wherein one, two, three, or four atoms in theheteroaryl ring system are independently oxygen, nitrogen, or sulfur, asvalency permits.
 33. The compound of claim 31, wherein Ring A is asubstituted or unsubstituted, bicyclic heteroaryl ring with onenitrogen.
 34. The compound of claim 31, wherein Ring A is of Formula(A-i):

wherein: each instance of R^(A1) is independently selected from thegroup consisting of hydrogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, and a nitrogen protecting group; and each instance of R^(A2)is independently selected from the group consisting of hydrogen,halogen, substituted or unsubstituted acyl, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —CN, —OR^(A2a),—N(R^(A2a))₂, and —SR^(A2a), wherein each occurrence of R^(A2a) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a nitrogen protecting groupwhen attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, and a sulfur protecting group when attachedto a sulfur atom, or two R^(A2a) groups are joined to form a substitutedor unsubstituted heterocyclic ring.
 35. The compound of claim 31,wherein Ring A is of the formula:


36. The compound of claim 31, wherein Ring A is a substituted orunsubstituted, bicyclic heteroaryl ring with two nitrogen.
 37. Thecompound of claim 31, wherein Ring A is of Formula (A-ii):

wherein: each instance of R^(A1) is independently selected from thegroup consisting of hydrogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, and a nitrogen protecting group; and each instance of R^(A2)is independently selected from the group consisting of hydrogen,halogen, substituted or unsubstituted acyl, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —CN, —OR^(A2a),—N(R^(A2a))₂, and —SR^(A2a), wherein each occurrence of R^(A2a) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a nitrogen protecting groupwhen attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, and a sulfur protecting group when attachedto a sulfur atom, or two R^(A2a) groups are joined to form a substitutedor unsubstituted heterocyclic ring.
 38. The compound of claim 31,wherein Ring A is of the formula:


39. The compound of claim 31, wherein Ring A is of Formula (A-iii):

wherein: each instance of R^(A1) is independently selected from thegroup consisting of hydrogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, and a nitrogen protecting group; and each instance of R^(A2)is independently selected from the group consisting of hydrogen,halogen, substituted or unsubstituted acyl, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —CN, —OR^(A2a),—N(R^(A2a))₂, and —SR^(A2a), wherein each occurrence of R^(A2a) isindependently selected from the group consisting of hydrogen,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a nitrogen protecting groupwhen attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, and a sulfur protecting group when attachedto a sulfur atom, or two R^(A2a) groups are joined to form a substitutedor unsubstituted heterocyclic ring.
 40. The compound of claim 31,wherein Ring A is of the formula:


41. The compound of any one of claims 1-30, wherein Ring A is asubstituted or unsubstituted, monocyclic heteroaryl ring.
 42. Thecompound of claim 41, wherein Ring A is a substituted or unsubstituted,5- or 6-membered, monocyclic heteroaryl ring, wherein one, two, three,or four atoms in the heteroaryl ring system are independently oxygen,nitrogen, or sulfur, as valency permits.
 43. The compound of claim 41,wherein Ring A is a substituted or unsubstituted, monocyclic heteroarylring with one nitrogen.
 44. The compound of claim 41, wherein Ring A isof Formula (A-v):

wherein: each instance of R^(A2) is independently selected from thegroup consisting of hydrogen, halogen, substituted or unsubstitutedacyl, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —OR^(A2a), —N(R^(A2a))₂, and —SR^(A2a), wherein eachoccurrence of R^(A2a) is independently selected from the groupconsisting of hydrogen, substituted or unsubstituted acyl, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogenprotecting group when attached to a nitrogen atom, an oxygen protectinggroup when attached to an oxygen atom, and a sulfur protecting groupwhen attached to a sulfur atom, or two R^(A2a) groups are joined to forma substituted or unsubstituted heterocyclic ring.
 45. The compound ofclaim 41, wherein Ring A is of the formula:


46. The compound of any one of claims 1-45, wherein L¹ is a bond. 47.The compound of any one of claims 1-45, wherein L¹ is —O—.
 48. Thecompound of any one of claims 1-45, wherein L¹ is —S—.
 49. The compoundof any one of claims 1-45, wherein L¹ is —NR^(c)—.
 50. The compound ofclaim 49, wherein L¹ is —NH—.
 51. The compound of any one of claims1-50, wherein R^(B1) is hydrogen.
 52. The compound of any one of claims1-50, wherein R^(B1) is —N(R^(a))₂.
 53. The compound of claim 52,wherein R^(B1) is —NH₂.
 54. The compound of any one of claims 1-53,wherein R^(B2) is hydrogen.
 55. The compound of any one of claims 1-54,wherein X is —NR^(c)—.
 56. The compound of claim 55, wherein X is —NH—.57. The compound of any one of claims 1-56, wherein Ring C is asubstituted or unsubstituted phenyl ring.
 58. The compound of any one ofclaims 1-56, wherein Ring C is a substituted or unsubstituted,monocyclic carbocyclic ring.
 59. The compound of claim 58, wherein RingC is a substituted or unsubstituted, 3- to 7-membered, monocycliccarbocyclic ring, wherein there are zero, one, or two double bonds inthe carbocyclic ring system, as valency permits.
 60. The compound ofclaim 58, wherein Ring C is substituted or unsubstituted cyclohexylene.61. The compound of any one of claims 1-56, wherein Ring C is asubstituted or unsubstituted, monocyclic heterocyclic ring.
 62. Thecompound of claim 61, wherein Ring C is a substituted or unsubstituted,3- to 7-membered, monocyclic heterocyclic ring, wherein one, two, orthree atoms in the heterocyclic ring system are independently oxygen,nitrogen, or sulfur, as valency permits.
 63. The compound of claim 61,wherein Ring C is substituted or unsubstituted piperidinylene.
 64. Thecompound of any one of claims 1-56, wherein Ring C is a substituted orunsubstituted, monocyclic heteroaryl ring.
 65. The compound of claim 64,wherein Ring C is a substituted or unsubstituted, 5- or 6-membered,monocyclic heteroaryl ring, wherein one, two, three, or four atoms inthe heteroaryl ring system are independently oxygen, nitrogen, orsulfur, as valency permits.
 66. The compound of claim 64, wherein Ring Cis substituted or unsubstituted pyridinylene.
 67. The compound of claim64, wherein Ring C is substituted or unsubstituted 2-pyridinylene,wherein X is attached to the 1-position of the substituted orunsubstituted 2-pyridinylene.
 68. The compound of any one of claims1-67, wherein L² is —NR^(c)C(═O)— or —C(═O)NR^(c)—.
 69. The compound ofclaim 68, wherein L² is —NR^(c)C(═O)—.
 70. The compound of claim 68,wherein L² is —NHC(═O)— or —C(═O)NH—.
 71. The compound of claim 68,wherein L² is —NHC(═O)—.
 72. The compound of any one of claims 1-67,wherein L² is —C(═O)—.
 73. The compound of any one of claims 1-67,wherein L² is —C(R^(b))₂—.
 74. The compound of claim 73, wherein L² is—CH₂—.
 75. The compound of any one of claims 1-67, wherein L² is—C(R^(b))₂C(═O)—.
 76. The compound of claim 75, wherein L² is—CH₂C(═O)—.
 77. The compound of any one of claims 1-67, wherein L² is—C(R^(b))₂C(═O)NR^(c)—.
 78. The compound of claim 77, wherein L² is—CH₂C(═O)NH—.
 79. The compound of any one of claims 1-78, wherein X andL² are para to each other.
 80. The compound of any one of claims 1-78,wherein X and L² are meta to each other.
 81. The compound of any one ofclaims 1-80, wherein R^(E) and L² are para to each other.
 82. Thecompound of any one of claims 1-80, wherein R^(E) and L² are meta toeach other.
 83. The compound of any one of claims 1-82, wherein Ring Dis a substituted or unsubstituted phenyl ring.
 84. The compound of anyone of claims 1-82, wherein Ring D is a substituted or unsubstituted,monocyclic carbocyclic ring.
 85. The compound of claim 84, wherein RingD is a substituted or unsubstituted, 3- to 7-membered, monocycliccarbocyclic ring, wherein there are zero, one, or two double bonds inthe carbocyclic ring system, as valency permits.
 86. The compound ofclaim 84, wherein Ring D is substituted or unsubstituted cyclohexylene.87. The compound of any one of claims 1-82, wherein Ring D is asubstituted or unsubstituted, monocyclic heterocyclic ring.
 88. Thecompound of claim 87, wherein Ring D is a substituted or unsubstituted,3- to 7-membered, monocyclic heterocyclic ring, wherein one, two, orthree atoms in the heterocyclic ring system are independently oxygen,nitrogen, or sulfur, as valency permits.
 89. The compound of claim 87,wherein Ring D is substituted or unsubstituted piperidinylene.
 90. Thecompound of any one of claims 1-89, wherein R^(E) is of Formula (i-18):


91. The compound of claim 90, wherein L is —NR^(c)C(═O)—.
 92. Thecompound of claim 90, wherein L³ is —NHC(═O)—.
 93. The compound of anyone of claims 90-92, wherein R^(E1) is hydrogen.
 94. The compound of anyone of claims 90-93, wherein R^(E2) is hydrogen.
 95. The compound of anyone of claims 90-94, wherein R^(E3) is optionally substituted alkyl. 96.The compound of claim 95, wherein R^(E3) is substituted alkyl.
 97. Thecompound of claim 95, wherein R^(E3) is —CH₂—N(CH₃)₂.
 98. The compoundof claim 90, wherein R^(E) is of the formula:


99. The compound of claim 90, wherein R^(E) is of the formula:


100. The compound of claim 1, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 101. The compound ofclaim 1, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 102. The compound ofclaim 1, wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 103. A pharmaceuticalcomposition comprising a compound of any one of claims 1-102, or apharmaceutically acceptable salt thereof, and optionally apharmaceutically acceptable excipient.
 104. The pharmaceuticalcomposition of claim 103, wherein the pharmaceutical compositioncomprises a therapeutically effective amount of the compound for use intreating a proliferative disease in a subject in need thereof.
 105. Amethod of treating a proliferative disease in a subject in need thereof,the method comprising administering to the subject a therapeuticallyeffective amount of a compound of any one of claims 1-102, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of any one of claims 103 and
 104. 106. The method of claim105, wherein the subject is a mammal.
 107. The method of claim 105,wherein the subject is a human.
 108. The method of any one of claims105-107, wherein the proliferative disease is associated with aberrantactivities of a kinase.
 109. The method of any one of claims 105-108,wherein the proliferative disease is cancer.
 110. The method of claim109, wherein the cancer is breast cancer.
 111. The method of claim 109,wherein the cancer is lung cancer.
 112. The method of claim 109, whereinthe cancer is small cell lung cancer (SCLC).
 113. The method of claim109, wherein the cancer is non-small cell lung cancer (NSCLC).
 114. Amethod of modulating the activity of a kinase in a biological sample orsubject, the method comprising administering to the subject orcontacting the biological sample with a therapeutically effective amountof a compound of any one of claims 1-102, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of any one ofclaims 103 and
 104. 115. The method of any one of claims 108 and 114,wherein the kinase is a protein kinase.
 116. The method of claim 115,wherein the protein kinase is a cyclin-dependent kinase (CDK).
 117. Themethod of claim 116, wherein the protein kinase is CDK7.
 118. The methodof claim 116, wherein the protein kinase is CDK12.
 119. The method ofclaim 116, wherein the protein kinase is CDK13.
 120. The method of anyone of claims 108 and 114, wherein the kinase is a lipid kinase. 121.The method of claim 120, wherein the lipid kinase is aphosphatidylinositol phosphate kinase (PIPK).
 122. The method of claim121, wherein the PIPK is PIP4K2.
 123. The method of claim 121, whereinthe PIPK is PI5P4Kα.
 124. The method of claim 121, wherein the PIPK isPI5P4Kβ.
 125. The method of claim 121, wherein the PIPK is PI5P4Kγ. 126.The method of any one of claims 105-125, wherein the compound is capableof covalently modifying Cys293 of PI5P4Kα.
 127. The method of any one ofclaims 105-125, wherein the compound is capable of covalently modifyingCys307 and/or Cys318 of PI5P4Kβ.
 128. The method of any one of claims105-125, wherein the compound is capable of covalently modifying Cys313of PI5P4Kγ.
 129. A method of inhibiting cell growth in a biologicalsample or subject, the method comprising administering to the subject orcontacting the biological sample with a therapeutically effective amountof a compound of any one of claims 1-102, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of any one ofclaims 103 and
 104. 130. The method of any one of claims 105-129,further comprising administering to the subject or contacting thebiological sample with a therapeutically effective amount of one or morepharmaceutical agents in combination with the compound, thepharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition.
 131. The method of claim 130, wherein the pharmaceuticalagent is an anti-proliferative agent.
 132. The method of claim 130,wherein the pharmaceutical agent is a kinase inhibitor.
 133. The methodof claim 130, wherein the pharmaceutical agent is an inhibitor of aprotein kinase.
 134. The method of claim 130, wherein the pharmaceuticalagent is an inhibitor of cyclin-dependent kinase (CDK).
 135. The methodof claim 130, wherein the pharmaceutical agent is an inhibitor of alipid kinase.
 136. The method of claim 130, wherein the pharmaceuticalagent is an inhibitor of a phosphatidylinositol phosphate kinase (PIPK).137. A kit comprising: a compound of any one of claims 1-102, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of any one of claims 103 and 104; and instructions foradministering to a subject or contacting a biological sample with thecompound, or a pharmaceutically acceptable salt thereof, or thepharmaceutical composition.